Xanthine phosphodiesterase V inhibitors

ABSTRACT

A xanthine phosphodiesterase V inhibitor having the formula (I), with the variables defined herein, which is especially useful for treating male (erectile) and female sexual dysfunction and other physiological disorders: 
     
       
         
         
             
             
         
       
     
     For example, a representative compound of the invention is:

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of, and claims the benefitof U.S. application Ser. No. 09/940,760, filed Aug. 28, 2001, now U.S.Pat. No. 6,821,978, which claims the benefit of U.S. ProvisionalApplication Ser. No. 60,233,567, filed Sep. 19, 2000.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to polycyclic nucleotide xanthinephosphodiesterase V inhibitors.

2. Description of Related Art

Phosphodiesterase (“PDE”) V inhibitor compounds are described by KennethJ. Murray in Phosphodiesterase V _(A) Inhibitors, DN & P 6(3), pp.150-156 (April, 1993), which is hereby incorporated herein by referencein its entirety, to have potential therapeutic value for a number ofphysiological disorders. One compound disclosed in the Murray article isMIMAX, a polycyclic xanthine PDE V inhibitor substituted at its8-position with a —NHCH₃ group.

U.S. Pat. No. 5,409,934, which is hereby incorporated herein byreference in its entirety, discloses a series of xanthine PDE Vinhibitors that are substituted at the 8-position with, among otherpossibilities, one of the following groups: —NO₂, —NR^(s)R^(t) or—NR⁶SO₂R⁵, where R^(s) and R^(t), independently of one another, are eacha hydrogen atom or an alkyl group, or R^(s) and R^(t), together with thenitrogen atom to which they are both attached, form a phthalimido group,R⁵ is an alkyl or aryl group, and R⁶ is a hydrogen atom or —SO₂R⁷, whereR⁷ is an alkyl or aryl group.

U.S. Pat. No. 5,470,579, which is hereby incorporated herein byreference in its entirety, discloses a xanthine PDE V inhibitor having asubstituted or unsubstituted —NH₂ group at the 8-position, for example,—NHR, where R is a C₁-C₆ alkyl group.

WO 93/23401, which is hereby incorporated herein by reference in itsentirety, discloses xanthine PDE V inhibitors that are substituted atthe 8-position with —NH(CH₂)₂CH(CH₂OR⁴)₂.

WO 92/05176, which is hereby incorporated herein by reference in itsentirety, discloses 8-acylaminoxanthine PDE V inhibitors that aresubstituted at the 8-position with —NHCOC₆H₅COOH.

WO 92/05175, which is hereby incorporated herein by reference in itsentirety, discloses 8-aminoxanthine PDE V inhibitors that aresubstituted at the 8-position with —NH₂ or —NHR, where R is an alkyl,arylalkyl or unsaturated heterocyclic (e.g., heteroaryl) group.

Specific PDE V inhibitors have been found useful for specificindications. For example, the use of PDE V inhibitors for treatingimpotence has met with commercial success with the introduction ofsildenafil citrate, better known as Viagra® (Pfizer, NY, N.Y.). Thechemistry and use of Viagra®, including its mechanism of action intreating erectile dysfunction, are taught in EP 0 702 555 B1, which ishereby incorporated herein by reference in its entirety. Additional PDEV inhibitors useful for treating erectile dysfunction are disclosed inWO 99/24433, which is hereby incorporated herein by reference in itsentirety.

Erectile dysfunction is a treatable and highly recognized healthconcern, affecting more than 30 million men in the United States,including one in four over age 65. Erectile dysfunction occurs when aman consistently is unable to sustain an erection sufficient forconducting sexual intercourse. In the past, psychological reasons werethe most common explanation for erectile dysfunction or it wasconsidered a natural part of aging. However, researchers todayacknowledge that more than 70 percent of instances of erectiledysfunction are due to physical or medical problems. There are severalfactors that may contribute to erectile dysfunction, including:

-   -   Poor blood circulation—atherosclerosis or hardening of the        arteries, high blood pressure and high cholesterol.    -   Neurological disorders—multiple sclerosis, Alzheimer's disease        and Parkinson's disease.    -   Hormone imbalances—diabetes, thyroid disorders and low        testosterone levels.    -   Trauma—spinal cord injury, prostate surgery or other trauma to        the pelvic area.    -   Prescription and over-the-counter medications—blood pressure        medications, antidepressants and certain drug combinations.    -   Lifestyle habits—smoking, alcohol abuse and using illegal drugs.

U.S. Pat. Nos. 5,939,419 and 5,393,755, both of which are herebyincorporated herein by reference in their entirety, disclose polycyclicguanine PDE V derivatives that are useful for the treatment ofcardiovascular and pulmonary disorders.

As has been shown by the representative art cited above, certainxanthine/guanine PDE V inhibitors have been found to be useful fortreating cardiovascular and pulmonary disorders, while some others havebeen found useful for treating impotence. It has been further shown thatcertain xanthine PDE V inhibitors can be substituted at the 8-positionby a variety of groups, including nitro and unsubstituted or substitutedamino groups. The substituted amino groups include saturatedheterocycles, where the nitrogen atom and its substituents together forman unsaturated heterocyclic group (e.g., —NR^(x)R^(y) can form aheterocycle).

It is an object of this invention to provide a polycyclic xanthine PDE Vinhibitor that possesses beneficial therapeutic properties.

It is a further object of the invention to provide a polycyclic xanthinePDE V inhibitor that has especially useful pharmacological properties.

It is yet another object of the invention to provide a polycyclicxanthine PDE V inhibitor that has good metabolic stability.

It is still another object of the invention to provide a polycyclicxanthine PDE V inhibitor that is effective for treating a variety ofphysiological symptoms and diseases in which PDE V plays a role.

It is also an object of the invention to provide a polycyclic xanthinePDE V inhibitor that is especially effective for treating erectiledysfunction with minimal side effects.

These and other objects of the invention will become apparent as thedescription progresses.

Definitions and Usage of Terms

The following definitions and terms are used herein or are otherwiseknown to a skilled artisan. Except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Thesedefinitions apply regardless of whether a term is used by itself or incombination with other terms, unless otherwise indicated. Hence, thedefinition of “alkyl” applies to “alkyl” as well as the “alkyl” portionsof “hydroxyalkyl,” “haloalkyl,” “alkoxy,” etc.

The term “chemically-compatible,” as used herein, means that asubstituent or variable in a structure, process or the like is selectedto be capable of resulting in a stable compound.

The term “substituted” or the phrase “with . . . one or moresubstituents,” as used herein, means the replacement of one or moreatoms or radicals, usually hydrogen atoms, in a given structure with achemically-compatible atom(s) or radical(s) selected from a specifiedgroup. In the situations where more than one atom or radical may bereplaced with substituents selected from the same specified group, thesubstituents may be, unless otherwise specified, either the same ordifferent at every position. Radicals of specified groups, such asalkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl,heterocycloalkyl, aryl and heteroaryl groups, independently of ortogether with one another, may be substituents for any substitutedgroup, unless otherwise known, stated or shown to be to the contrary.

Representative substituents for alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, heteroaryl andheterocycloalkyl groups include, but are not limited to, the followingmoieties: alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl,alkylaryl, aryl, heteroaryl, heterocycloalkyl, hydroxyalkyl, arylalkyl,aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl,imidazolylalkyl, indolylalkyl, mono-, di- and trihaloalkyl, mono-, di-and trihaloalkoxy, amino, alkylamino, dialkylamino, alkoxy, hydroxy,halo (e.g., —Cl and —Br), nitro, oximino, —COOR⁵⁰, —COR⁵⁰, —SO₀₋₂R⁵⁰,—SO₂NR⁵⁰R⁵¹, NR⁵²SO₂R⁵⁰, ═C(R⁵⁰R⁵¹), ═N—OR⁵⁰, ═N—CN, ═C(halo)₂, ═S, ═O,—CON(R⁵⁰R⁵¹), —OCOR⁵⁰, —OCON(R⁵⁰R⁵¹), —N(R⁵²)CO(R⁵⁰), —N(R⁵²)COOR⁵⁰ and—N(R⁵²)CON(R⁵⁰R⁵¹), where:

-   -   R⁵⁰, R⁵¹ and R⁵² may be independently selected from the        following: a hydrogen atom and a branched or straight-chain,        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₄₋₆ heterocycloalkyl, heteroaryl        and aryl group, with or without substituents. When permissible,        R⁵⁰ and R⁵¹ can be joined together to form a carbocyclic or        heterocyclic ring system. R⁵⁰, R⁵¹ and R⁵² may also include:

where,

-   -   R⁴⁰ and R⁴¹ are, independently of one another, each a hydrogen        atom or a branched or straight-chain, optionally substituted,        alkyl, cycloalkyl, heterocycloalkyl, halo, aryl,        imidazolylalkyl, indolylalkyl, heteroaryl, arylalkyl,        arylalkoxy, heteroarylalkyl, heteroarylalkoxy, aminoalkyl,        haloalkyl, mono-, di- or trihaloalkyl, mono-, di- or        trihaloalkoxy, nitro, cyano, alkoxy, hydroxy, amino, phosphino,        phosphate, alkylamino, dialkylamino, formyl, alkylthio,        trialkylsilyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl,        aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl,        morpholino, thioalkyl, alkylthioalkyl, carboxyalkyl, oximino,        —COOR⁵⁰, —COR⁵⁰, —SO₀₋₂R⁵⁰, —SO₂NR⁵⁰R⁵¹, —NR⁵²SO₂R⁵⁰,        —CON(R⁵⁰R⁵¹), —OCON(R⁵⁰R⁵¹), —N(R⁵²)CO(R⁵⁰), —N(R⁵²)COOR⁵⁰,        —N(R⁵²)CON(R⁵⁰R⁵¹) or —OCONR⁵⁰ group, where, R⁵⁰, R⁵¹ and R⁵²        are as defined above;    -   R⁴² is a hydrogen atom or a branched or straight-chain,        optionally substituted, alkyl, alkenyl, arylalkyl or acyl group;        and    -   R⁴³ is a hydrogen atom or a branched or straight-chain,        optionally substituted, alkyl or aryl group;    -   wherein, the optional substituents are defined the same as above        for the one or more substituents.

Preferred substituents on aryl and heteroaryl groups include, but arenot limited to, any of the moieties recited above in the definition forR⁴⁰ and R⁴¹.

The term “heteroatom,” as used herein, means a nitrogen, sulfur, oroxygen atom. Multiple heteroatoms in the same group may be the same ordifferent.

The term “hydrocarbon,” as used herein, means a compound or radicalconsisting of only carbon and hydrogen atoms, including aliphatic,aromatic, normal, saturated and unsaturated hydrocarbons.

The term “alkyl,” as used herein, means an unsubstituted or substituted,straight or branched, hydrocarbon chain (i.e., comprising carbon andhydrogen atoms bonded together), having, preferably, from one totwenty-four carbon atoms, more preferably, from one to twelve carbonatoms, and most preferably, from one to eight carbon atoms.

The term “cycloalkyl” or “cycloalkane,” as used herein, means anunsubstituted or substituted, saturated, stable non-aromatic carbocyclicring, having, preferably, from three to fifteen carbon atoms, morepreferably, from three to eight carbon atoms. The carbon ring radical issaturated and may be fused, for example, benzofused, with one to threecycloalkyl, aromatic, heterocyclic or heteroaromatic rings. Thecycloalkyl may be attached at any endocyclic carbon atom that results ina stable structure. Preferred carbocycles have from five to six carbons.Examples of carbocycle radicals include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and the like.

The term “alkenyl,” as used herein, means an unsubstituted orsubstituted, unsaturated, straight or branched, hydrocarbon chain havingat least one double bond present and, preferably, from two to fifteencarbon atoms, more preferably, from two to twelve carbon atoms.

The term “cycloalkenyl,” as used herein, means an unsubstituted orsubstituted, unsaturated carbocyclic ring having at least one doublebond present and, preferably, from three to fifteen carbon atoms, morepreferably, from five to eight carbon atoms. A cycloalkenyl group is anunsaturated carbocyclic group. Examples of cycloalkenyl groups includecyclopentenyl and cyclohexenyl.

The term “alkynyl,” as used herein, means an unsubstituted orsubstituted, unsaturated, straight or branched, hydrocarbon chain havingat least one triple bond present and, preferably, from two to twelvecarbon atoms, more preferably, two to ten carbon atoms.

The term “bicycloalkyl,” as used herein, represents a saturated linearlyfused or bridged carbocyclic ring having, preferably, from 5 to 12carbon atoms.

The term “aryl,” as used herein, means a substituted or unsubstituted,aromatic, mono- or bicyclic carbocyclic ring system having from one totwo aromatic rings. The aryl moiety will generally have from 6 to 14carbon atoms with all available substitutable carbon atoms of the arylmoiety being intended as possible points of attachment. Representativeexamples include phenyl, tolyl, xylyl, cumenyl, naphthyl,tetrahydronaphthyl, indanyl, indenyl and the like. If desired, thecarbocyclic moiety can be substituted with from one to five, preferably,one to three moieties, such as mono- through pentahalo, alkyl,trifluoromethyl, phenyl, hydroxy, alkoxy, phenoxy, amino,monoalkylamino, dialkylamino and the like.

The term “heteroaryl,” as used herein, means a mono- or bicyclic ringsystem containing one or two aromatic rings and at least one nitrogen,oxygen or sulfur atom in an aromatic ring. Heteroaryl groups (includingbicyclic heteroaryl groups) can be unsubstituted or substituted with aplurality of substituents, preferably, one to five substituents, morepreferably, one, two or three substituents (e.g., mono- throughpentahalo, alkyl, trifluoromethyl, phenyl, hydroxy, alkoxy, phenoxy,amino, monoalkylamino, dialkylamino and the like). Typically, aheteroaryl group represents a cyclic group of five or six atoms, or abicyclic group of nine or ten atoms, at least one of which is carbon,and having at least one oxygen, sulfur or nitrogen atom interrupting acarbocyclic ring having a sufficient number of pi (π) electrons toprovide aromatic character. Representative heteroaryl (heteroaromatic)groups are pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl,benzofuranyl, thienyl, benzothienyl, thiazolyl, thiadiazolyl,imidazolyl, pyrazolyl, triazolyl, isothiazolyl, benzothiazolyl,benzoxazolyl, oxazolyl, pyrrolyl, isoxazolyl, 1,3,5-triazinyl andindolyl groups.

The term “arylalkyl,” as used herein, means an alkyl moiety substitutedwith an optionally substituted, aryl or heteroaryl group. Representativearylalkyl groups include a benzyl group and fused bicyclic systems whichcontain one aryl group.

The term “alkylaryl,” as used herein, means an aryl or heteroaryl moietysubstituted with an optionally substituted, alkyl group. Representativealkylaryl groups include o-, m- and p-linked tolyl and xylyl groups.

Unless otherwise known, stated or shown to be to the contrary, the pointof attachment for a multiple term substituent (multiple terms that arecombined to identify a single moiety) to a subject structure is throughthe last named term of the multiple term. For example, an “arylalkyl”substituent attaches to a targeted structure through the “alkyl” portionof the substituent. Conversely, when the substituent is “alkylaryl”, itattaches to a targeted structure through the “aryl” portion of thesubstituent. Similarly, a cycloalkylalkyl substituent attaches to atargeted through the latter “alkyl” portion of the substituent (e.g.,Structure-alkyl-cycloalkyl).

The term “heterocycloalkyl,” as used herein, means an unsubstituted orsubstituted, saturated cyclic ring system having from three to fifteenmembers, preferably, from three to eight members, and comprising carbonatoms and at least one heteroatom as part of the ring.

The term “heterocyclic ring” or “heterocycle,” as used herein, means anunsubstituted or substituted, saturated, unsaturated or aromatic ring,comprised of carbon atoms and one or more heteroatoms in the ring.Heterocyclic rings may be monocyclic or polycyclic. Monocyclic ringspreferably contain from three to eight atoms, most preferably, five toseven atoms. Polycyclic ring systems consisting of two rings preferablycontain from six to sixteen atoms, most preferably, ten to twelve atoms.Polycyclic ring systems consisting of three rings contain, preferably,from thirteen to seventeen atoms, most preferably, fourteen to fifteenatoms. Each heterocyclic ring has at least one hetero atom. Unlessotherwise stated, the heteroatoms may be independently selected from thefollowing: nitrogen, sulfur and oxygen atoms.

The term “carbocyclic ring” or “carbocycle,” as used herein, means anunsubstituted or substituted, saturated, unsaturated or aromatic (e.g.,aryl), hydrocarbon ring, unless otherwise specifically identified.Carbocycles may be monocyclic or polycyclic. Monocyclic rings preferablycontain from three to eight atoms, most preferably, five to seven atoms.Polycyclic rings having two rings preferably contain from six to sixteenatoms, most preferably, ten to twelve atoms, and those having threerings preferably contain from thirteen to seventeen atoms, mostpreferably, fourteen to fifteen atoms.

The term “alkoxy,” as used herein, means an oxygen atom bonded to ahydrocarbon chain, such as an alkyl or alkenyl group (e.g., —O-alkyl or—O-alkenyl). Representative alkoxy groups include methoxy, ethoxy, andisopropoxy groups.

The term “hydroxyalkyl,” as used herein, means a substituted hydrocarbonchain, preferably, an alkyl group, having at least one hydroxy,substituent (i.e., —OH). Additional substituents to the alkyl group mayalso be present. Representative hydroxyalkyl groups includehydroxymethyl, hydroxyethyl and hydroxypropyl groups.

The term “carboxyalkyl,” as used herein, means a substituted hydrocarbonchain, preferably, a substituted alkyl group, which has a carboxylsubstituent (e.g., —COOH) and may also have additional substituents(such as one of the representative substituents identified above for theterm “substituted”). Representative carboxyalkyl groups includecarboxymethyl (—CH₂CO₂H) and carboxyethyl (—CH₂CH₂CO₂H) groups, andderivatives thereof, such as the corresponding esters.

The term “aminoalkyl,” as used herein, means an alkyl group substitutedwith an amine moiety (e.g., -alkylNH₂), such as aminomethyl.

The term “alkylamino,” as used herein, means an amino moiety having fromone or two alkyl substituents (e.g., —NH-alkyl), such as dimethylamino.

The term “alkenylamino,” as used herein, means an amino moiety havingfrom one or two alkenyl substituents, where the nitrogen atom of theamino group is not attached to the alkene-forming carbon atom (e.g.,—NH—CH₂-alkenyl), such as dibutenylamino.

The term “arylamino,” as used herein, means an amine moiety substitutedwith an aryl group (i.e., —NH-aryl).

The term “alkylimino,” as used herein, means an imino moiety having onealkenyl or two alkyl substituents (e.g., —C═N-alkyl).

The term “oximino,” as used herein, means compounds containing the—C═N—OR⁶⁹ radical, where R⁶⁹ is a hydrogen atom or an alkyl or arylgroup.

The term “aroyl,” as used herein, means the radical R—CO—; where R is anaromatic group. Representative aroyls are benzoyl and naphthoyl.

The term “aryloxy,” as used herein, means an oxygen atom having an arylsubstituent (e.g., —O-aryl).

The term “ester,” as used herein, means compounds containing asubstituted carboxylic acid (e.g., —COO-aryl).

The term “acyl” or “carbonyl,” as used herein, means a carbon to oxygendouble bond, (e.g., R—C(═O)—), which can be a radical of a carboxylicacid having the formula alkyl-CO—, aryl-CO—, arylalkyl-CO—,cycloalkyl-CO—, alkylcycloalkyl-CO— or heteroaryl-CO—. Representativeacyl groups include acetyl, propionyl, butanoyl and benzoyl groups.

The term “acyloxy,” as used herein, means an oxygen atom having an acylsubstituent (e.g., —O-acyl), for example, —O—C(═O)-alkyl.

The term “acylamino,” as used herein, means an amino moiety having anacyl substituent (e.g., —NH-acyl), for example, an amide with theformula —NH—(C═O)-alkyl, a urea with the formula —NH—(C═O)—NH-alkyl or acarbamate with the formula —NH—(C═O)—OR, where R is an alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl orheterocycloalkyl group.

The term “halo,” “halogen” or “halide,” as used herein, means a chloro,bromo, fluoro or iodo atom radical. Chlorides, bromides and fluoridesare preferred halides.

The term “lower hydrocarbon” (e.g., “lower alkyl”), as used herein,means a hydrocarbon chain comprised of from, unless otherwise stated,one to eight carbon atoms, preferably, one to six carbon atoms, and mostpreferably, one to four carbon atoms.

The term “polyhalo,” as used herein, represents substitution of at leasttwo halo atoms to a group modified by the term “polyhalo.”

The term “aminosulfonyl,” as used herein, represents a group having theformula: —SO₂NR⁷⁹R⁸⁹, where R⁷⁹ and R⁸⁹ are, independently of oneanother, each a hydrogen atom or a lower alkyl (e.g., from 1 to 6 carbonatoms) or aryl group.

The term “sulfonyl,” as used herein, represents a group having theformula: —S(O)₂—.

When a variable appears more than once in a structural formula, forexample, R⁵⁹ for where X is —C(OR⁵⁹)₂—, the identity of each variableappearing more than once may be independently selected from thedefinition for that variable.

The term “prodrug,” as used herein, represents a compound that is a drugprecursor, which following administration to a patient, releases a drugin vivo via some kind of chemical and/or physiological process (e.g., aprodrug on being brought to a physiological pH and/or through an enzymeaction is converted to a desired drug form).

The term “compound of the formula (I.1) or (II.1)”, as used herein,represents a compound having a chemical structure encompassed by theformula (I.1) or (II.1), and includes any and all enantiomers,stereoisomers, rotomers, tautomers and prodrugs of the compound.Compounds of the formula (I.1) or (II.1) also include theircorresponding pharmaceutically-acceptable salts, solvates, esters andderivatives.

The term “pharmaceutically-acceptable excipients,” as used herein,includes any physiologically inert, pharmacologically inactive materialknown to one skilled in the art, which is compatible with the physicaland chemical characteristics of the particular active ingredientselected for use. Pharmaceutically-acceptable excipients includepolymers, resins, plasticizers, fillers, binders, lubricants, glidants,disintegrates, solvents, co-solvents, buffer systems, surfactants,preservatives, sweetening agents, flavoring agents, pharmaceutical gradedyes or pigments, and viscosity agents.

The term “pharmaceutical composition,” as used herein, means acombination of at least one inventive compound (e.g., PDE V inhibitor)and at least one pharmaceutically-acceptable excipient.

The terms “compound [having the formula (I)] or a pharmaceuticalcomposition thereof” include neutral, acidic and alkaline forms of thecompound or composition, as well as solvates, esters and salts (as aredefined below) thereof, and further includes derivatives of theinventive compounds.

The term “pharmaceutically-acceptable salt,” as used herein, means acationic salt formed at an acidic (e.g., carboxyl) group or an anionicsalt formed at a basic (e.g., amino) group of the compound. Many suchsalts are known in the art, for example, those that are described in WO87/05297 (1987), which is hereby incorporated in its entirety byreference herein. Preferred cationic salts include the alkali-metalsalts (e.g., sodium and potassium) and alkaline earth metal salts (e.g.,magnesium and calcium). Preferred anionic salts include the halide(e.g., chloride), acetate and phosphate salts.

The phrase “effective amount,” as used herein, means an amount of acompound or composition which is sufficient to significantly andpositively modify the symptoms and/or conditions to be treated (e.g.,provide a positive clinical response). The phrase “safe and effectiveamount,” as used herein, means that an “effective amount” must also besafe, that is, an amount that is sufficient to provoke a positiveresponse, yet is small enough to avoid serious side effects (at areasonable benefit/risk ratio), within the scope of sound medicaljudgment. The effective amount of an active ingredient for use in apharmaceutical composition will vary with the particular condition beingtreated, the severity of the condition, the duration of the treatment,the nature of concurrent therapy, the particular active ingredient beingemployed, the particular pharmaceutically-acceptable excipients utilizedand like factors within the knowledge and expertise of the attendingphysician.

The phrase “administering [to a patient a safe and effective amount ofthe inventive compound],” as used herein, refers to any mode ofintroducing any form (e.g., solid, liquid or gas) of the inventivecompounds in vivo to a patient (e.g., human or mammal). For example,introduction of the inventive compound to a patient may be accomplishedvia oral ingestion (e.g., tablets, capsules, gels, solutions, etc.),adsorption, absorption (e.g., transmucosal sublingual or buccaladministration), transdermal applications (e.g., topical applicationsvia patches, lotions, etc.), suppositories, etc.

The term “oral dosage form,” as used herein, means any pharmaceuticalcomposition intended to be systemically administered to an individual bydelivering the composition to the gastrointestinal tract of anindividual, via the mouth of the individual. For purposes of theinvention, the delivered form can be a tablet (coated or non-coated),solution, suspension or capsule (coated or non-coated).

The term “injection,” as used herein, means any pharmaceuticalcomposition intended to be systemically administered to a human or othermammal, via delivery of a solution or emulsion containing the activeingredient, by puncturing the skin of said individual, in order todeliver the solution or emulsion to the circulatory system of theindividual either by intravenous, intramuscular, intraperitoneal orsubcutaneous injection.

Other than as shown in the operating examples or where is otherwiseindicated, all numbers used in the specification and claims expressingquantities of ingredients, reaction conditions, and so forth, areunderstood as being modified in all instances by the term “about.”

SUMMARY OF THE INVENTION

The invention comprises a compound having the formula (I):

where,

-   -   (a) R¹ and R² are, independently of one another, each a C₁₋₁₅        alkyl group, branched or straight chain, with or without one or        more substituents, such as a hydroxy or alkoxy substituent        group, a C₂₋₁₅ alkenyl group, branched or straight chain, with        or without one or more substituents, a C₂₋₁₅ alkynyl group,        branched or straight chain, with or without one or more        substituents, a C₃₋₁₅ cycloalkyl group, with or without one or        more substituents, an arylalkyl group, with or without one or        more substituents, an aryl group, with or without one or more        substituents, a heteroaryl group, with or without one or more        substituents, —OR⁵, —COOR⁵, —C(O)R⁵ or —C(O)N(R⁵)₂, where R⁵ is        a hydrogen atom or a hydrocarbon radical, with or without one or        more substituents, preferably, R⁵ is a hydrogen atom or an alkyl        group, branched or straight chain, with or without one or more        substituents; or        -   one of R¹ and R² is equal to a hydrogen atom, and the other            one of R¹ and R² is defined the same as above;    -   (b) R³ is an aryl group, with or without one or more        substituents, such as a hydroxy alkoxy substituent group, a        heteroaryl group, with or without one or more substituents, or a        heterocyclic group having from 1 to 3 heteroatoms fused to a 5-        or 6-membered aryl ring, with or without one or more        substituents, with the proviso that R³ is not an aryl group        substituted at its para position with a —Y-aryl group, where Y        is a carbon-carbon single bond, —CO—, —O—, —S—, —N(R²¹)—,        —CON(R²²)—, —N(R²²)CO—, —OCH₂—, —CH₂O—, —SCH₂—, —CH₂S—,        —NHC(R²³) (R²⁴)—, —NR²³SO₂—, —SO₂NR²³—, —C(R²³) (R²⁴)NH—,        —CH═CH—, —CF═CF—, —CH═CF—, —CF═CH—, —CH₂CH₂—, —CF₂CF₂—,

where,

-   -   R²¹ is a hydrogen atom or a —CO(C₁₋₄ alkyl), C₁₋₆ alkyl, allyl,        C₃₋₆ cycloalkyl, phenyl or benzyl group;    -   R²² is a hydrogen atom or a C₁₋₆ alkyl group;    -   R²³ is a hydrogen atom or a C₁₋₅ alkyl, aryl or —CH₂-aryl group;    -   R²⁴ is a hydrogen atom or a C₁₋₄ alkyl group;    -   R²⁵ is a hydrogen atom or a C₁₋₈ alkyl, C₁₋₈ perfluoroalkyl,        C₃₋₆ cycloalkyl, phenyl or benzyl group;    -   R²⁶ is a hydrogen atom or a C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl        or benzyl group;    -   R²⁷ is —NR²³R²⁴, —OR²⁴, —NHCONH₂, —NHCSNH₂,

and

-   -   R²⁸ and R²⁹ are, independently of one another, each a C₁₋₄ alkyl        group or, taken together, a —(CH₂)_(q)— group, where q is 2 or        3;    -   Wherein, R²¹ through R²⁹ are with or without one or more        substituents; and    -   (c) R⁴ is a C₃₋₁₅ cycloalkyl group, with or without        substituents, such as a hydroxy substituent group, a C₃₋₁₅        cycloalkenyl group, with or without one or more substituents, or        a heterocycloalkyl group of 3 to 15 members, with or without one        or more substituents;

wherein, the optional one or more substituents for all the groups arechemically-compatible and are, independently of one another, eachdefined the same as recited above in the definition section.

The invention comprises at least one compound of the formula (I), whichincludes any and all enantiomers, stereoisomers, rotomers, tautomers andprodrugs of the at least one inventive compound. Compounds of theformula (I) also include their corresponding salts, solvates (e.g.,hydrates), esters, and the like. The invention further comprisespharmaceutically-acceptable compositions prepared from an inventivecompound or a mixture of inventive compounds, or a salt, solvate orester thereof. The compounds of formula (I) can be useful for treating avariety of diseases, symptoms and physiological disorders, such assexual dysfunction, especially impotence (e.g., erectile dysfunction).

A further understanding of the invention will be had from the followingdescription of preferred embodiments.

DESCRIPTION OF PREFERRED EMBODIMENTS

The inventive compounds having the formula (I) are substituted at the8-position on the chemical structure with an amino group that itself issubstituted with one of the following groups: an unsaturated orsaturated carbocyclic group and a saturated heterocyclic group. Theinventive substituted xanthines exhibited unexpectedly enhancedproperties with respect to enzyme activity and enzyme selectivity. It isbelieved that the substitution at the 8-position of the subject PDE Vinhibitor compounds with these specific groups, helped produceunexpectedly highly potent and selective xanthines, which exhibitedincreased isozyme selectivity when compared to conventional xanthines.Pharmaceutical compositions comprising the inventive compounds possessunexpectedly superior therapeutic properties.

Referring above to the inventive xanthine PDE V inhibitor compoundshaving the formula (I), the 8-position on the chemical structure issubstituted with a —NHR⁴ group, where R⁴ represents a carbocyclic orheterocyclic system defined as follows: a C₃₋₁₅ cycloalkyl group, aC₃₋₁₅ cycloalkenyl group or a heterocycloalkyl group of 3 to 15 members.All of the cyclic systems are optionally substituted. Preferredsubstituents on the cyclic systems include a C₃₋₆ cycloalkyl group, aC₁₋₆ alkoxy C₁₋₆ alkyl group, a C₁₋₆ alkyl group, an amino C₁₋₆ alkylgroup, a C₁₋₆ dialkylamino C₁₋₆ alkyl group, a C₃₋₆ dicycloalkylaminoC₁₋₆ alkyl group, a hydroxy group, an alkoxy group, an oximino group,—COR⁶, —SO₂R⁶, —COOR⁶, —CONR⁶R⁷, —SO₂NR⁶R⁷, —N(R⁸)SO₂R⁶ and —NR⁶R⁷,where:

-   -   R⁶ is a hydrogen atom or an optionally substituted, C₁₋₆ alkyl,        C₃₋₆ cycloalkyl, C₃₋₆ heterocycloalkyl, aryl or heteroaryl        group;    -   R⁷ is a hydrogen atom or an optionally substituted, C₁₋₆ alkyl,        C₃₋₆ cycloalkyl, C₃₋₆ heterocycloalkyl, aryl or heteroaryl        group; or    -   R⁶ and R⁷, when applicable, may be joined together to form a        heterocyclic ring system; and    -   R⁸ is a hydrogen atom or an optionally substituted, C₁₋₆ alkyl,        C₃₋₆ cycloalkyl, C₃₋₆ heterocycloalkyl, aryl or heteroaryl        group.

Furthermore, R⁴ may also be substituted with —ZR⁷⁰Z′—, where R⁷⁰,together with Z and Z′, form a spiro-fused 5- to 7-membered ring or alinearly fused 4- to 7-membered ring system, and Z and Z′, independentlyof one another, are each an oxygen, sulfur or nitrogen atom. Forexample, when Z═Z′═O, R⁴ may be substituted by the following structurehaving the formula (VIII):

Preferred substituents are defined above for the groups. Othersubstituents may also be used, such as ketones, oximes, cyclic systems,including lineraly fused and bridged, mono-, bi- and tricyclic rings,spiro-cyclic systems, including ketals and thioketals directly attachedto R⁴, halogens and sulfonamides. One skilled in the art can determineother possible substituents depending on the conditions employed and thedesired properties.

A preferred structure of the invention is represented by formula (II):

where,

-   -   R¹, R² and R³ are defined the same as above for the compound of        formula (I);    -   R⁹ is one of the following atoms or groups:        -   (a) a hydrogen atom;        -   (b) an oximino group;        -   (c) a carboxyalkyl group;        -   (d) a C₁₋₆ alkoxy C₁₋₆ alkyl group;        -   (e) an aryloxy C₁₋₆ alkyl group;        -   (f) a C₃₋₆ cycloalkoxy C₁₋₆ alkyl group;        -   (g) a heteroaryloxy C₁₋₆ alkyl group;        -   (h) a —COOH group;        -   (i) an ester group;        -   (j) a C₁₋₆ alkyl group;        -   (k) a C₃₋₆ cycloalkyl group;        -   (l) a C₃₋₆ heterocyclic group;        -   (m) a hydroxy C₁₋₆ alkyl group;        -   (n) an aryl group; or        -   (o) a heteroaryl group;            wherein, all of the above groups are optionally substituted;    -   R¹⁰ and R¹¹ are substituents on the same or different carbon        atoms of the ring and, independently of one another, are each        defined the same as above for R⁹ and, additionally, may each be        one of the following groups:        -   (a) a hydroxy group;        -   (b) an ester group derived from a hydroxy group with a:            -   (i) C₁₋₆ carboxylic acid;            -   (ii) C₃₋₆ cycloalkyl C₁₋₆ carboxylic acid;            -   (iii) aryl C₁₋₆ carboxylic acid; or            -   (iv) heteroaryl C₁₋₆ carboxylic acid group;        -   (c) a C₁₋₆ alkoxy group;        -   (d) an amino group;        -   (e) a C₁₋₆ mono- or dialkylamino group;        -   (f) a C₁₋₆ alkylacylamino group;        -   (g) a C₁₋₆ alkylsulfonylamino group; or        -   (h) a —NHCON(R¹⁴)₂ group, where R¹⁴ is a hydrogen atom or an            optionally substituted, alkyl or aryl group; or    -   R¹⁰ and R¹¹, taken together with each other and, optionally,        with one or more carbon and/or hetero atoms of the ring, form an        optionally substituted, spiro-fused, linearly fused, bi- or        tri-cyclic ring system of from 8 to 12 members, including from 0        to 4 hetero atoms, where, all of the above R¹⁰, R¹¹ and R¹⁴        groups are optionally substituted;    -   m and n are, independently of one another, each from 1 to 3; and    -   X is a chemcially-compatible group, which is —C(R¹⁰R¹¹)—,        —S(O)_(y), —O—, —N(R⁶⁰)—, where:        -   R¹⁰ and R¹¹ are, independently of one another, each defined            the same as previously;        -   y is from 0 to 2;        -   R⁶⁰ is a hydrogen atom or a C₁₋₈ alkyl, C₁₋₈ alkynyl, C₁₋₈            alkenyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, C₄₋₈            heterocycloalkyl, COR⁶¹, SO₂R⁶¹, COOR⁶¹, CONR⁶¹R⁶² or            SO₂NR⁶¹R⁶² group, with or without substituents, where:            -   R⁶¹ is a hydrogen atom or a C₁₋₈ alkyl, C₁₋₈ alkynyl,                C₁₋₈ alkenyl, C₃₋₈ cycloalkyl, aryl, heteroaryl or C₄₋₈                heterocyclic group, with or without substituents;            -   R⁶² is a hydrogen atom or a C₁₋₈ alkyl, C₁₋₈ alkynyl,                C₁₋₈ alkenyl, C₃₋₈ cycloalkyl, aryl, heteroaryl or C₄₋₈                heterocyclic group, with or without substituents; and            -   when R⁶¹ and R⁶² are (the same or different) alkyl                groups, they can, if desired, be joined together to form                a carbocyclic or heterocyclic ring system;    -   wherein, the optional substituents and the one or more        substituents are defined the same as for the one or more        substituents of formula (I) above.

In the compound of formula (II), the different carbon atoms to which R¹⁰and R¹¹ may be connected can be adjacent or non-adjacent. Preferably,R⁹, R¹⁰ and R¹¹ are all hydrogen atoms. In another embodiment of theinvention, one of R¹⁰ or R¹¹ is, advantageously, a hydroxy group.

In the compounds of formulas (I) and (II), R¹ is, preferably, an alkylgroup or an arylalkyl group, particularly, a benzyl group. Morepreferably, R¹ is a lower alkyl group of from 1 to 4 carbon atoms, andmost preferably, a methyl or ethyl group.

R², in the compounds of formulas (I) and (II), is, preferably, an alkylgroup, particularly, an alkyl group substituted with a hydroxy group.More preferably, R² is a lower alkyl group of from 1 to 3 carbon atomsor a hydroxyalkyl group, and most preferably, R² is a methyl, ethyl,iso-butyl or hydroxyethyl group.

In the compounds of formulas (I) and (II), R³ is, preferably, an arylgroup, particularly, an aryl group substituted with a hydroxy-, alkoxy-or amino-sulfonyl group, which may be, advantageously, substituted with1 or 2 halogen atoms. When R³ is a heteroaryl group in the compounds offormulas (I) and (II), it is generally preferable to utilize heteroarylgroups other than furan. Most preferably, R³ is a methoxyaryl groupsubstituted on its aryl ring with at least one halogen atom, forexample, a substitution with 1 or 2 halogen atoms, such as chlorine orbromine. For instance, R³ can be 4-hydroxyphenyl,3-chloro-4-hydroxyphenyl, 3-bromo-4-hydroxyphenyl, 4-methoxyphenyl,3-chloro-4-methoxyphenyl, 3-bromo-4-methoxyphenyl, 4-aminosulfonylphenylgroup, 3-chloro-4-aminosulfonylphenyl group or3-bromo-4-aminosulfonyl-phenyl.

R⁴, in the compound of formula (I), is, preferably, a cycloalkyl orheterocycloalkyl group, particularly, a cycloalkyl group substitutedwith a hydroxy group. More preferably, R⁴ is a cyclohexyl,hydroxycyclopentyl or tetrahydropyranyl group. Most preferably, R⁴ is ahydroxycyclopentyl group. For instance, R⁴ can be a2(R)-hydroxy-1(R)-cyclopentyl group. All of the preferred embodimentsmay be unsubstituted or substituted.

The compounds of formulas (I) and (II) are useful for treatingurogenital diseases, such as male (e.g., impotence/erectile dysfunction)and female sexual dysfunction. The following compounds listed in TablesI and II are illustrative of the invention:

TABLE I Compound No. Structure 10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

TABLE II Compound No. STRUCTURE HRMS Calc. HRMS Found M, M + 1 100

439.2821 439.2821 (M + 1) 101

412.2349 412.2346 (M + 1) 102

526.3213 526.3203 (M+) 103

442.2454 442.2451 (M + 1) 104

428.2298 428.2294 (M + 1) 105

476.2065 476.2057 (M + 1) 106

478.1857 478.1851 (M + 1) 107

462.1908 462.191 (M + 1) 108

490.1857 490.1853 (M + 1) 109

492.1650 492.1641 (M + 1) 110

455.2533 455.2518 (M+) 111

458.2403 458.2395 (M + 1) 112

442.2454 442.2448 (M + 1) 113

444.2247 444.2252 (M + 1) 114

522.1352 522.1346 (M + 1) 115

464.1701 464.1696 (M + 1) 116

506.1403 506.141 (M + 1) 117

520.1559 520.1568 (M + 1) 118

508.1196 508.119 (M + 1) 119

475.2128 475.2134 (M + 1) 120

429.1932 429.1931 (M+) 121

488.2332 488.2333 (M + 1) 122

504.1610 504.1605 (M + 1) 123

506.1403 506.1395 (M + 1) 124

522.1542 522.1542 (M + 1) 125

520.1559 520.1552 (M + 1) 126

477.1920 477.1919 (M + 1) 127

477.1920 477.1914 (M + 1) 128

536.1335 536.1335 (M + 1) 129

522.1352 522.136 (M + 1) 130 no structure n/a n/a n/a 131

382.2243 382.2242 (M + 1) 132

382.2243 382.2238 (M + 1) 133

424.2713 424.2717 (M + 1) 134

396.2400 396.2396 (M + 1) 135

396.2400 396.2393 (M + 1) 136

386.1992 386.1988 (M + 1) 137

386.1992 386.1988 (M + 1) 138

386.1992 386.1985 (M + 1) 139

398.2192 398.2196 (M + 1) 140

382.2243 382.2238 (M + 1) 141

398.2192 398.2192 (M + 1) 142

412.1985 412.1982 (M + 1) 143

428.2298 428.2294 (M + 1) 144

412.2349 412.2346 (M + 1) 145

384.2036 384.2041 (M + 1) 146

384.2036 384.2033 (M + 1) 147

398.2192 398.2184 (M + 1) 148

402.1697 402.1691 (M + 1) 149

493.0975 493.098 (M+) 150

451.1831 451.1819 (M+) 151

435.1882 435.1879 (M+) 152

446.1192 446.1187 (M + 1) 153

435.1229 435.1219 (M+) 154

404.1898 404.1895 (M + 1) 155

428.2298 428.2292 (M + 1) 156

420.1603 420.1603 (M + 1) 157

413.1937 413.1932 (M + 1) 158

444.2400 444.2394 (M + 1) 159

431.1724 431.173 (M+) 160

446.1595 446.1588 (M + 1) 161

418.1646 418.164 (M + 1) 162

436.1960 436.1962 (M + 1) 163

436.1960 436.1957 (M + 1) 164

452.1909 452.1919 (M + 1) 165

414.2305 414.2303 (M + 1) 166

440.2662 440.2657 (M + 1) 167

426.2505 426.2509 (M + 1) 168

440.2298 440.2295 (M + 1) 169

426.2505 426.2498 (M + 1) 170

412.2349 412.2345 (M + 1) 171

474.2272 474.2277 (M + 1) 172

459.2037 459.2055 (M+) 173

428.2462 428.2457 (M + 1) 174

440.2662 440.2657 (M + 1) 175

454.2454 454.2449 (M + 1) 176

454.2818 454.2812 (M + 1) 177

426.2505 426.2503 (M + 1) 178

440.2662 440.2666 (M + 1) 179

509.1738 509.1729 (M + 1) 180

555.1233 555.123 (M + 1) 181

511.153 511.1524 (M + 1) 182

491.2077 491.2087 (M + 1) 183

525.1687 525.1697 (M + 1) 184

571.1164 571.1138 (M + 1) 185

538.1492 538.1498 (M + 1) 186

524.1335 524.1344 (M + 1) 187

575 575 (M)LRMS 188

477.192 477.1919 (M + 1) 189

477.192 477.1919 (M + 1) 190

557.1007 557.0997 (M + 1) 191

511.153 511.1519 (M + 1) 192

494.1637 494.1636 (M + 1) 193

510.1578 510.1574 (M + 1) 194

554.1073 554.1066 (M + 1) 195

525.159 525.1582 (M + 1) 196

525.159 525.1597 (M + 1) 197

478.168 478.1683 (M + 1) 198

522.1174 522.1169 (M + 1) 199

542.1405 542.143 (M + 1)

The compounds of the invention are useful for inhibiting PDE V enzymes.Their enzyme activities and enzyme selectivities can be evaluated in anumber of ways. In particular, enzyme activity can be measured by thePDE V IC₅₀ value, which is the concentration (in nM) of the compoundrequired to provide 50% inhibition of PDE V. The lower the value ofIC₅₀, the more active is the compound. Measurements on the compounds inTables I and II gave the following data (all numbers are modified by theword “about”):

-   -   A. all compounds had a PDE V IC₅₀ within the range of from <1 nM        to >100 nM;    -   B. compound nos. 13-18, 25, 30-32, 38, 41-43, 55-58, 69-71, 77,        85, 92, 96, 98, 101, 113, 120, 121, 126, 128, 131, 137, 138,        141, 146-48, 165, 166, 173, 176, 181, 182, 184, 185, 193 and 194        had a PDE V IC₅₀ within the range of from >15 to 100 nM;    -   C. compound nos. 23, 24, 29, 33, 34, 39, 40, 93, 94, 108, 111,        112, 125, 136, 144, 160 and 161 had a PDE V IC₅₀ within the        range of from >10 to 15 nM.    -   D. compound nos. 21, 22, 28, 36, 37, 59, 66, 68, 78, 79, 89, 95,        99, 110, 115, 132, 159, 171, 172, 175, 180, 183, 190 and 199 had        a PDE V IC₅₀ within the range of from >5 to 10 nM; and    -   E. compound nos. 60-65, 67, 103-07, 114, 116-19, 122-24, 142,        168-70, 177, 178, 179, 186-88, 191, 197 and 198 had a PDE V IC₅₀        within the range of up to 5 nM.

In addition, another type of measurement that can be made is the ratioof PDE VI IC₅₀/PDE V IC₅₀ (identified as “PDE VI/PDE V”), which is anindicator of enzyme selectivity—the higher the ratio, the more selectiveis the compound to inhibiting PDE V enzyme relative to PDE VI enzyme.Measurements on the compounds (except for compound nos. 189, 192, 195and 196) in Table II gave the following data (all numbers are modifiedby the word “about”):

-   -   F. compound nos. 1-188, 190, 191, 193, 194 and 197-99 had a PDE        VI/PDE V ratio of >0;    -   G. compound nos. 165 and 193 had a PDE VI/PDE V ratio within the        range of from >0 to 10;    -   H. compound nos. 101, 108, 136, 141, 146, 148, 168, 173 and 194        had a PDE VI/PDE V ratio within the range of from >10 to 25;    -   I. compound nos. 104, 125, 131-32, 137-38, 142, 144, 170, 175,        177, 185 and 199 had a PDE VI PDE V ratio within the range of        from >25 to 50;    -   J. compound nos. 103, 110, 111, 117, 159, 166, 182 and 187 had a        PDE VI/PDE V ratio within the range of from >50 to 75;    -   K. compound nos. 105, 106, 147 and 171 had a PDE VI/PDE V ratio        within the range of from >75 to 100;    -   L. compound nos. 112, 113, 123, 124, 126, 169, 172 and 184 had a        PDE VI/PDE V ratio within the range of from >100 to 140; and    -   M. compound nos. 107, 114-16, 118-22, 128, 160-61, 176, 178-81,        183, 186, 188, 190, 191, 197 and 198 had a PDE VI/PDE V ratio of        from >140.

Preferred compounds of the invention include those found in classes Eand/or M: compound nos. 60-65, 67, 103-07,114-24, 128, 142,160-61,168-70, 176-78, 179, 186, 188, 191, 197 and 198. More preferredcompounds of the invention are compound nos. 107, 114, 116, 118, 119,122, 160, 178 and 186 of Table II.

Another preferred compound of the invention would have the followingchemical structure:

Specific and general procedures for producing three preferred compoundsfollow below (compound nos. 107, 114 and 160). Obvious modifications tothese procedures may be undertaken by one of ordinary skill in the art.Other compounds of the invention may be produced along the same lines.

Synthesis of Compound No. 107 in Table II (7)

Preparation of 9

Experimental Procedure: Compound No. 107 in Table II (7)

1 (20.0 g, 74.0 mmol) was dissolved in dimethylformamide (370 mL) undernitrogen and (2-bromoethoxy)-tert-butyldimethylsilane (31.8 mL, 148mmol) was added dropwise. The reaction was stirred at room temperaturefor 115 hrs., then diluted with ethyl acetate and washed with waterseveral times. The organic mixture was dried over potassium carbonate,filtered and concentrated under vacuum. Purification via flashchromatography (30/70 ethyl acetate/hexanes) yielded 2 (28.1 g, 88%).

¹H NMR (400 MHz, CDCl₃): δ 7.52 (s, 1H), 7.29-7.39 (m, 5H), 5.49 (s,2H), 4.25 (t, 2H, J=6.0 Hz), 4.07 (q, 2H, J=7.2 Hz), 3.93 (t, 2H, J=6.0Hz), 1.24 (t, 3H, J=7.2 Hz), 0.75 (s, 9H), 0.08 (s, 6H). HRMS: Calcd forC₂₂H₃₂N₄O₃Si (M+H): 429.2322. Found: 429.2329.

To a solution of 2 (2.10 g, 4.89 mmol) in methanol (375 mL) was addedammonium formate (4.64 g, 73.6 mmol) and 20% palladium hydroxide oncarbon (980 mg). The reaction was heated to reflux for 1.5 hrs., thencooled to room temperature, filtered and concentrated under vacuum.Purification via flash chromatography (50/50 ethyl acetate/hexanes)yielded 3 (1.26 g, 94%).

¹H NMR (400 MHz, CDCl₃): δ 7.82 (s, 1H), 4.33 (t, 2H, J=6.0 Hz), 4.16(q, 2H, J=7.2 Hz), 3.99 (t, 2H, J=6.0 Hz), 1.29 (t, 3H, J=7.2 Hz), 0.78(s, 9H), 0.06 (s, 6H). HRMS: Calcd for C₁₅H₂₆N₄O₃Si (M+H): 339.1852.Found: 339.1864.

To 3 (970 mg, 2.86 mmol) was added dimethylformamide (14 mL),3-chloro-4-methoxybenzyl bromide 9 (1.72 g, 5.70 mmol), and potassiumcarbonate (785 mg, 5.70 mmol) under nitrogen. The reaction mixture wasstirred at room temperature for 24 hrs., then diluted with ethyl acetateand washed with water several times. The organic mixture was dried overpotassium carbonate, filtered and concentrated under vacuum.Purification by flash chromatography (30/70 ethyl acetate/hexanes)yielded 4 (1.14 g, 81%).

¹H NMR (400 MHz, CDCl₃): δ 7.52 (s, 1H), 7.33 (d, 1H, J=2.4 Hz), 7.25(dd 1H, J=2.0 Hz, J=8.4 Hz), 6.90 (d, 1H, J=8.8 Hz), 5.40 (s, 2H), 4.25(t, 2H, J=6.0 Hz), 4.07 (q, 2H, J=7.2 Hz), 3.93 (t, 2H, J=6.0 Hz), 3.89(s, 3H), 1.25 (t, 3H, J=7.2 Hz), 0.75 (s, 9H), 0.08 (s, 6H). HRMS: Calcdfor C₂₃H₃₃ClN₄O₄Si (M+H): 493.2038. Found: 493.2032.

To solution of 4 (1.14 g, 2.32 mmol) in tetrahydrofuran (20 mL) undernitrogen at −78° C. (dry ice/acetone bath) was added lithiumdiisopropylamide (2M in THF/heptane, 1.7 mL, 3.48 mmol). After stirringfor thirty minutes, 1,2-dibromotetrafluoroethane (0.55 mL, 4.63 mmol)was added dropwise over five minutes. The reaction was stirred for 1.5hrs. at −78° C. then quenched with saturated aqueous sodium bicarbonateand warmed to room temperature. The mixture was extracted withdichloromethane, dried over potassium carbonate, filtered andconcentrated under vacuum. Purification via flash chromatography (30/70ethyl acetate/hexanes) yielded 5 (640 mg, 48%).

¹H NMR (400 MHz, CDCl₃): δ 7.42 (d, 1H, J=2.4 Hz), 7.31 (dd, 1H, J=2.0Hz, J=8.4 Hz), 6.88 (d, 1H, J=8.8 Hz), 5.45 (s, 2H), 4.22 (t, 2H, J=5.6Hz), 4.07 (q, 2H, J=7.2 Hz), 3.92 (t, 2H, J=5.6 Hz), 3.88 (s, 3H), 1.25(t, 3H, J=7.2 Hz), 0.74 (s, 9H), 0.08 (s, 6H). HRMS: Calcd forC₂₃H₃₂BrClN₄O₄Si (M+H): 571.1143. Found: 571.1149.

To 5 (320 mg, 0.56 mmol) was added cyclohexylamine (0.25 mL, 2.24 mmol),diisopropylethylamine (2.8 mL), and 1-methyl-2-pyrrolidinone (2.8 mL).The reaction mixture was heated to 160° C. in a sealed tube for 18 hrs.,then cooled to room temperature. Water was added, then the mixture wasextracted with ethyl acetate and washed with water several times. Theorganic mixture was dried over potassium carbonate, filtered andconcentrated under vacuum. Purification via flash chromatography (30/70ethyl acetate/hexanes) yielded 6 (210 mg, 64%).

¹H NMR (400 MHz, CDCl₃): δ 7.27 (d, 1H, J=2.0 Hz), 7.13 (dd, 1H, J=2.0Hz, J=8.4 Hz), 6.89 (d, 1H, J=8.8 Hz), 5.23 (s, 2H), 4.19 (t, 2H, J=6.2Hz), 4.05 (q, 2H, J=7.2 Hz), 3.93 (t, 2H, J=6.2 Hz), 3.89 (s, 3H),3.86-3.91 (m, 1H), 3.69-3.80 (m, 1H), 1.88-1.96 (m, 2H), 1.52-1.64 (m,3H), 1.28-1.42 (m, 2H), 1.23 (t, 3H, J=7.2 Hz), 1.04-1.22 (m, 3H), 0.81(s, 9H), 0.01 (s, 6H). HRMS: Calcd for C₂₉H₄₄ClN₅O₄Si (M+H): 590.2937.Found: 590.2929.

6 (191 mg, 0.324 mmol) was dissolved in dichloromethane (4.0 mL) undernitrogen and cooled to 0° C. in an ice bath. Boron tribromide (0.14 mL,1.42 mmol) was added to the reaction mixture and warmed to roomtemperature. After 1.25 hr., the reaction was diluted withdichloromethane and washed with water several times. The organic phasewas dried over potassium carbonate, filtered and concentrated undervacuum. Purification via PTLC (70/30 ethyl acetate/hexanes) yielded 7(compound no. 107 in Table II) (122 mg, 74%).

¹H NMR (400 MHz, CDCl₃): δ 7.25-7.28 (m, 1H), 7.09 (dd, 1H, J=2.0 Hz,J=8.0 Hz), 7.01 (d, 1H, J=8.0 Hz), 5.69 (s, 1H), 5.23 (s, 2H), 4.32-4.36(m, 2H), 4.16 (t, 1H, J=6.0 Hz), 4.06 (q, 2H, J=7.2 Hz), 3.90-3.98 (m,3H), 3.62-3.72 (m, 1H), 1.87-1.96 (m, 2H), 1.54-1.66 (m, 3H), 1.31-1.43(m, 2H), 1.25 (t, 3H, J=7.2 Hz), 1.06-1.22 (m, 3H). HRMS: Calcd forC₂₂H₂₈ClN₅O₄ (M+H): 462.1908. Found: 462.1901.

3-Chloro-4-methoxytoluene 8 (2.6 mL, 19.2 mmol) was dissolved indichlomethane (30 mL) and N-bromosuccinimide (3.75 g, 21.1 mmol) wasadded followed by AIBN (36.0 mg). The reaction was heated to reflux for19 hrs., then cooled to room temperature and the precipitate wasfiltered off. The filtrate was diluted with dichloromethane and washedwith 0.5 M aqueous sodium bicarbonate, followed by water. The organicmixture was dried over sodium sulfate, filtered and concentrated undervacuum to yield 9 (4.73 g, 82%). The benzyl bromide was used as thecrude material without further purification.

¹H NMR (400 MHz, CDCl₃): δ 7.42 (d, 1H, J=2.4 Hz), 7.26 (dd, 1H, J=2.4Hz, J=8.4 Hz), 6.88 (d, 1H, J=8.4 Hz), 4.44 (s, 2H), 3.90 (s, 3H).

General Synthesis of Compound No. 107 in Table II (7)

a) Reacting 1 with an alkyl halide and base to form 2;

b) Debenzylation of 2 to form 3;

c) Alkylation of 3 with a benzyl halide to form 4;

d) Deprotonation of 4 followed by addition of a brominating agent toform 5;

e) Displacement of bromo 5 with an amine to form 6; and

f) Treatment of 6 with boron tribromide to form compound no. 107 inTable II (7) via cleavage of both silyl and methyl ethers.

Synthesis of Compound 114 in Table II (13)

Preparation of 15

Experimental Procedure: Compound 114 in Table II (13)

1 (20.0 g, 74.0 mmol) was dissolved in dimethylformamide (370 mL) undernitrogen and (2-bromoethoxy)-tert-butyldimethylsilane (31.8 mL, 148mmol) was added dropwise. The reaction was stirred at room temperaturefor 115 hrs., then diluted with ethyl acetate and washed with waterseveral times. The organic mixture was dried over potassium carbonate,filtered and concentrated under vacuum. Purification via flashchromatography (30/70 ethyl acetate/hexanes) yielded 2 (28.1 g, 88%).

¹H NMR (400 MHz, CDCl₃): δ 7.52 (s, 1H), 7.29-7.39 (m, 5H), 5.49 (s,2H), 4.25 (t, 2H, J=6.0 Hz), 4.07 (q, 2H, J=7.2 Hz), 3.93 (t, 2H, J=6.0Hz), 1.24 (t, 3H, J=7.2 Hz), 0.75 (s, 9H), 0.08 (s, 6H). HRMS: Calcd forC₂₂H₃₂N₄O₃Si (M+H): 429.2322. Found: 429.2329.

To a solution of 2 (2.10 g, 4.89 mmol) in methanol (375 mL) was addedammonium formate (4.64 g, 73.6 mmol) and 20% palladium hydroxide oncarbon (980 mg). The reaction was heated to reflux for 1.5 hrs., thencooled to room temperature, filtered and concentrated under vacuum.Purification via flash chromatography (50/50 ethyl acetate/hexanes)yielded 3 (1.26 g, 94%).

¹H NMR (400 MHz, CDCl₃): δ 7.82 (s, 1H), 4.33 (t, 2H, J=6.0 Hz), 4.16(q, 2H, J=7.2 Hz), 3.99 (t, 2H, J=6.0 Hz), 1.29 (t, 3H, J=7.2 Hz), 0.78(s, 9H), 0.06 (s, 6H). HRMS: Calcd for C₁₅H₂₆N₄O₃Si (M+H): 339.1852.Found: 339.1864.

To 3 (970 mg, 2.86 mmol) was added dimethylformamide (25 mL),3-bromo-4-methoxybenzyl bromide 15 (1.62 g, 5.79 mmol), and potassiumcarbonate (800 mg, 5.79 mmol) under nitrogen. The reaction mixture wasstirred at room temperature for 21 hrs., then diluted with ethyl acetateand washed with water several times. The organic mixture was dried overpotassium carbonate, filtered and concentrated under vacuum.Purification by flash chromatography (30/70 ethyl acetate/hexanes)yielded 10 (1.55 g, 100%).

¹H NMR (400 MHz, CDCl₃): δ 7.52 (s, 1H), 7.51 (d, 1H, J=2.4 Hz), 7.30(dd 1H, J=2.0 Hz, J=8.4 Hz), 6.87 (d. 1H. J=8.8 Hz), 5.40 (s, 2H), 4.25(t, 2H, J=6.0 Hz), 4.07 (q, 2H, J=7.0 Hz), 3.93 (t, 2H, J=6.0 Hz), 3.88(s, 3H), 1.25 (t, 3H, J=7.0 Hz), 0.75 (s, 9H), 0.08 (s, 6H). HRMS: Calcdfor C₂₃H₃₃BrN₄O₄Si (M+H): 537.1533. Found: 537.1540.

To solution of 10 (1.50 g, 2.80 mmol) in tetrahydrofuran (24 mL) undernitrogen at −78° C. (dry ice/acetone bath) was added lithiumdiisopropylamide (2M in THF/heptane, 2.2 mL, 4.33 mmol). After stirringfor thirty minutes, 1,2-dibromotetrafluoroethane (0.69 mL, 5.77 mmol)was added dropwise over five minutes. The reaction was stirred for 1.25hrs. at −78° C. then quenched with saturated aqueous sodium bicarbonateand warmed to room temperature. The mixture was extracted withdichloromethane, dried over potassium carbonate, filtered andconcentrated under vacuum. Purification via flash chromatography (30/70ethyl acetate/hexanes) yielded 11 (600 mg, 34%).

¹H NMR (400 MHz, CDCl₃): δ 7.60 (d, 1H, J=2.4 Hz), 7.35 (dd, 1H, J=2.0Hz, J=8.4 Hz), 6.84 (d, 1H, J=8.4 Hz), 5.45 (s, 2H), 4.21 (t, 2H, J=5.6Hz), 4.07 (q, 2H, J=6.8 Hz), 3.90 (t, 2H, J=5.6 Hz), 3.87 (s, 3H), 1.24(t, 3H, J=6.8 Hz), 0.73 (s, 9H), 0.08 (s, 6H). HRMS: Calcd forC₂₃H₃₂Br₂N₄O₄Si (M+H): 615.0638. Found: 615.0633.

To 11 (1.89 g, 3.07 mmol) was added the amino alcohol hydrochloride salt(1.31 g, 12.27 mmol), diisopropylethylamine (15.4 mL), and1-methyl-2-pyrrolidinone (15.4 mL). The reaction mixture was heated to160° C. in a sealed tube for 13 hrs., then cooled to room temperature.Water was added, then the mixture was extracted with ethyl acetate andwashed with water several times. The organic mixture was dried overpotassium carbonate, filtered and concentrated under vacuum.Purification via flash chromatography (3/97 methanol/dichloromethane)yielded 12 (1.77 g, 90%).

¹H NMR (400 MHz, CDCl₃): δ 7.45 (d, 1H, J=2.0 Hz), 7.17 (dd, 1H, J=2.4Hz, J=8.6 Hz), 6.86 (d, 1H, J=8.4 Hz), 5.18-4.34 (m, 3H), 4.00-4.23 (m,5H), 3.86-3.98 (m, 6H), 3.69-3.79 (m, 1H), 2.10-2.21 (m, 1H), 1.99-2.10(m, 1H), 1.60-1.84 (m, 3H), 1.32-1.43 (m, 1H), 1.24 (t, 3H, J=7.2 Hz),0.75 (s, 9H), 0.07 (d, 6H, J=4.0 Hz). HRMS: Calcd for C₂₈H₄₃BrN₅O₅Si(M+H): 636.2217. Found: 636.2207.

12 (1.77 g, 2.78 mmol) was dissolved in tetrahydrofuran (28 mL) undernitrogen and tetrabutylammonium fluoride (1M in THF, 28 mL) was addeddropwise. The reaction was stirred at room temperature for 15 hrs., thendiluted with dichloromethane and washed with water several times. Theorganic mixture was dried over potassium carbonate, filtered andconcentrated under vacuum. Purification via flash chromatography (3/97methanol/dichloromethane) yielded 13 (compound no. 114 in Table II) (760mg, 52%).

¹H NMR (400 MHz, CDCl₃): δ 7.47 (d, 1H, J=2.0 Hz), 7.19 (dd, 1H, J=2.0Hz, J=8.4 Hz), 6.88 (d, 1H, J=8.4 Hz), 5.25 (s, 2H), 5.09 (s, 1H),4.21-4.27 (m, 3H), 4.06 (q, 2H, J=7.0 Hz), 3.90-3.97 (m, 3H), 3.89 (s,1H), 3.74-3.82 (m, 1H), 3.08 (s, 1H), 2.12-2.22 (m, 1H), 1.98-2.08 (m,1H), 1.60-1.86 (m, 3H), 1.33-1.43 (m, 1H), 1.25 (t, 3H, J=7.0 Hz),1.06-1.22 (m, 3H). HRMS: Calcd for C₂₂H₂₈BrN₅O₅ (M+H): 522.1352. Found:522.1346.

2-Bromo-4-methyl anisole 14 (2.2 mL, 14.9 mmol) was dissolved indichlomethane (30 mL) and N-bromosuccinimide (3.75 g, 16.4 mmol) wasadded followed by AIBN (26.0 mg). The reaction was heated to reflux for19 hrs., then cooled to room temperature and the precipitate wasfiltered off. The filtrate was diluted with dichloromethane and washedwith 0.5 M aqueous sodium bicarbonate, followed by water. The organicmixture was dried over sodium sulfate, filtered and concentrated undervacuum to yield 15 (4.16 g, 100%). The benzyl bromide was used as thecrude material without further purification.

¹H NMR (400 MHz, CDCl₃): δ 7.59 (d, 1H, J=2.0 Hz), 7.30 (dd, 1H, J=2.4Hz, J=8.4 Hz), 6.85 (d, 1H, J=8.4 Hz), 4.37 (s, 2H), 3.90 (s, 3H).

General Synthesis of Compound No. 114 in Table II (13)

a) Reacting 1 with an alkyl halide and base to form 2;

b) Debenzylation of 2 to form 3;

c) Alkylation of 3 with a benzyl halide to form 10;

d) Deprotonation of 10 followed by addition of a brominating agent toform 11;

e) Displacement of bromo 11 with an amine to form 12; and

f) Silyl ether cleavage of 12 to form compound no. 114 in Table II (13).

Synthesis of Compound No. 160 in Table II (18)

Experimental Procedure: Compound No. 160 in Table II (18)

To 16 (150 mg, 0.579 mmol) was added dimethylformamide (3 mL),6-chloropiperonyl chloride (142 mg, 0.694 mmol) and potassium carbonate(120 mg, 0.868 mmol) under nitrogen. The reaction mixture was stirred atroom temperature for 137 hrs., then diluted with ethyl acetate andwashed with water several times. The organic mixture was dried overmagnesium sulfate, filtered and concentrated under vacuum. Purificationvia PTLC (1/1 ethyl acetate/hexanes) yielded 17 (84.1 mg, 34%).

¹H NMR (400 MHz, CDCl₃): δ 6.89 (s, 1H), 6.09 (s, 1H), 5.95 (s, 2H),5.59 (s, 2H), 3.60 (s, 3H), 3.38 (s, 3H). HRMS: Calcd for C₁₅H₁₂BrClN₄O₄(M+H): 426.9809. Found: 426.9802.

To 17 (72.0 mg, 0.169 mmol) was added cyclohexylamine (86.7 mg, 0.883mmol), diisopropylethylamine (0.8 mL) and 1-methyl-2-pyrrolidinone (0.8mL). The reaction mixture was heated to 160° C. in a sealed tube for 17hrs., then cooled to room temperature. Water was added, then the mixturewas extracted with ethyl acetate and washed with water several times.The organic mixture was dried over magnesium sulfate, filtered andconcentrated under vacuum. Purification via PTLC (1/1 ethylacetate/hexanes) yielded compound no. 160 in Table II (18) (50.9 mg,68%).

¹H NMR (400 MHz, CDCl₃): δ 6.84 (s, 1H), 6.815 (s, 1H), 5.96 (s, 2H),5.33 (s, 2H), 4.42 (d, 1H, J=7.2 Hz), 3.68-3.79 (m, 1H), 3.53 (s, 3H),3.40 (s, 3H), 1.94-2.05 (m, 2H), 1.55-1.74 (m, 3H), 1.25-1.42 (m, 2H),1.10-1.22 (m, 3H). HRMS: Calcd for C₂₁H₂₄ClN₅O₄ (M+H): 444.2400. Found:444.2394.

General Synthesis of Compound No. 160 in Table II (18)

a) Alkylation of 16 with a benzyl halide to form 17; and

b) Displacement of bromo 17 with an amine to form compound no. 160 inTable II (18).

Accordingly, the invention includes a method for producing a compoundhaving the formula (I), comprising:

-   -   (i) reacting a compound having the formula (III) with an alkyl        halide in the presence of a base to form a compound having the        formula (IV):

-   -   where,    -   (a) R¹ is a hydrogen atom or a C₁₋₁₅ alkyl group, branched or        straight chain, with or without one or more substituents, a        C₂₋₁₅ alkenyl group, branched or straight chain, with or without        one or more substituents, a C₂₋₁₅ alkynyl group, branched or        straight chain, with or without one or more substituents, a        C₃₋₁₅ cycloalkyl group, with or without one or more        substituents, an arylalkyl group, with or without one or more        substituents, an aryl group, with or without one or more        substituents, a heteroaryl group, with or without one or more        substituents, —OR⁵, —COOR⁵, —C(O)R⁵ or —C(O)N(R⁵)₂, where R⁵ is        a hydrogen atom or a hydrocarbon radical, branched or        straight-chain, with or without one or more substituents    -   (b) L is R² or a protected form of R²; and    -   (c) Ph is a phenyl group;    -   (ii) debenzylating and then alkylating the compound having the        formula (IV) with an alkyl halide, XCH₂R³, to form the compound        having the formula (V):

-   -   where,        -   X is a halogen atom (e.g., a chlorine or bromine atom) and        -   R³ is an aryl group, with or without one or more            substituents, a heteroaryl group, with or without one or            more substituents, or a heterocyclic group having 1 to 3            heteroatoms fused to a 5 or 6 membered aryl ring, with or            without one or more substituents, with the proviso that R³            is not an aryl group substituted at its para position with a            —Y-aryl group, where Y is a carbon-carbon single bond, —CO—,            —O—, —S—, —N(R²¹)—, —CON(R²²)—, —N(R²²)CO—, —OCH₂—, —CH₂O—,            —SCH₂—, —CH₂S—, —NHC(R²³)(R²⁴)—, —NR²³SO₂—, —SO₂NR²³—,            —C(R²³) (R²⁴)NH—, —CH═CH—, —CF═CF—, —CH═CF—, —CF═CH—,            —CH₂CH₂—, —CF₂CF₂—,

-   -   where,        -   R²¹ is a hydrogen atom or a —CO(C₁₋₄ alkyl), C₁₋₆ alkyl,            allyl, C₃₋₆ cycloalkyl, phenyl or benzyl group;        -   R²² is a hydrogen atom or a C₁₋₆ alkyl group;        -   R²³ is a hydrogen atom or a C₁₋₅ alkyl, aryl or —CH₂-aryl            group;        -   R²⁴ is a hydrogen atom or a C₁₋₄ alkyl group;        -   R²⁵ is a hydrogen atom or a C₁₋₈ alkyl, C₁₋₈ perfluoroalkyl;            C₃₋₆ cycloalkyl, phenyl or benzyl group;        -   R²⁶ is a hydrogen atom or a C₁₋₆ alkyl, C₃₋₆ cycloalkyl,            phenyl or benzyl group;        -   R²⁷ is —NR²³R²⁴, —OR²⁴, —NHCONH₂, —NHCSNH₂,

and

-   -   -   R²⁸ and R²⁹ are, independently of one another, each a C₁₋₄            alkyl group, or R²⁸ and R²⁹, taken together with each other,            are a —(CH₂)_(q) group, where q is 2 or 3;        -   wherein, R²¹ through R²⁹ are optionally substituted with any            of the groups defined above for the one or more            substituents; and

    -   (iii) deprotonating and then halogenating the compound having        the formula (V) to form a compound having the formula (VI):

-   -   where,        -   Hal is a halogen atom;    -   (iv) reacting the compound having the formula (VI) with an amine        having the formula R⁴NH₂ to form a compound having the formula        (VII):

-   -   where,        -   R⁴ is a C₃₋₁₅ cycloalkyl group, with or without one or more            substituents, a C₃₋₁₅ cycloalkenyl group, with or without            one or more substituents, or a heterocycloalkyl group of 3            to 15 members, with or without one or more substituents; and    -   (v) removing the protecting portion of L, when L is the        protected form of R², on the compound having the formula (VII)        to form the compound having the formula (I):

-   -   -   where,            -   R² is defined the same as R¹ above, with the proviso                that at least one of R¹ and R² is not a hydrogen atom;        -   wherein, the one or more substituents are defined the same            as for the one or more substituents of formula (I) above.

Pharmaceutically-Acceptable Dosage Forms

The compounds of the present invention may be administered to humans orother mammals by a variety of routes, including oral dosage forms andinjections (intravenous, intramuscular, intraperitoneal, subcutaneous,and the like). Numerous other dosage forms containing the compounds ofthe present invention can be readily formulated by one skilled in theart, utilizing the suitable pharmaceutical excipients as defined below.For considerations of patient compliance, oral dosage forms aregenerally most preferred.

The rate of systemic delivery can be satisfactorily controlled by oneskilled in the art, by manipulating any one or more of the following:

-   -   (a) the active ingredient proper;    -   (b) the pharmaceutically-acceptable excipient(s), so long as the        variants do not interfere in the activity of the particular        active ingredient selected;    -   (c) the type of excipient(s), and the concomitant desirable        thickness and permeability (swelling properties) of the        excipient(s);    -   (d) the time-dependent conditions of the excipient(s);    -   (e) the particle size of the granulated active ingredient; and    -   (f) the pH-dependent conditions of the excipient(s).

Pharmaceutically-acceptable excipients include flavoring agents,pharmaceutical-grade dyes or pigments, solvents, co-solvents, buffersystems, surfactants, preservatives, sweetener agents, viscosity agents,fillers, lubricants, glidants, disintegrants, binders and resins.

Conventional flavoring agents may be used, such as those described inRemington's Pharmaceutical Sciences, 18^(th) Ed., Mack Publishing Co.,pp. 1288-1300 (1990), which is incorporated in its entirety by referenceherein. The pharmaceutical compositions of the invention generallycontain from about 0 to 2% of flavoring agents.

Conventional dyes and/or pigments may also be used, such as thosedescribed in the Handbook of Pharmaceutical Excipients, by the AmericanPharmaceutical Association & the Pharmaceutical Society of GreatBritain, pp. 81-90 (1986), which is incorporated in its entirety byreference herein. The pharmaceutical compositions of the inventiongenerally contain from about 0 to 2% of dyes and/or pigments.

The pharmaceutical compositions of the invention generally contain fromabout 0.1 to 99.9% of solvent(s). A preferred solvent is water.Preferred co-solvents include ethanol, glycerin, propylene glycol,polyethylene glycol, and the like. The pharmaceutical compositions ofthe invention may include from about 0 to 50% of co-solvents.

Preferred buffer systems include acetic, boric, carbonic, phosphoric,succinic, malaic, tartaric, citric, acetic, benzoic, lactic, glyceric,gluconic, glutaric and glutamic acids and their sodium, potassium andammonium salts. Particularly preferred buffers are phosphoric, tartaric,citric and acetic acids and salts thereof. The pharmaceuticalcompositions of the invention generally contain from about 0 to 5% of abuffer.

Preferred surfactants include polyoxyethylene sorbitan fatty acidesters, polyoxyethylene monoalkyl ethers, sucrose monoesters and lanolinesters and ethers, alkyl sulfate salts and sodium, potassium andammonium salts of fatty acids. The pharmaceutical compositions of theinvention generally contain from about 0 to 2% of surfactants.

Preferred preservatives include phenol, alkyl esters ofparahydroxybenzoic acid, o-phenylphenol benzoic acid and salts thereof,boric acid and salts thereof, sorbic acid and salts thereof,chlorobutanol, benzyl alcohol, thimerosal, phenylmercuric acetate andnitrate, nitromersol, benzalkonium chloride, cetylpyridinium chloride,methyl paraben and propyl paraben. Particularly preferred preservativesare the salts of benzoic acid, cetylpyridinium chloride, methyl parabenand propyl paraben. The pharmaceutical compositions of the inventiongenerally include from about 0 to 2% of preservatives.

Preferred sweeteners include sucrose, glucose, saccharin, sorbitol,mannitol and aspartame. Particularly preferred sweeteners are sucroseand saccharin. Pharmaceutical compositions of the invention generallyinclude from about 0 to 5% of sweeteners.

Preferred viscosity agents include methylcellulose, sodiumcarboxymethylcellulose, hydroxypropyl-methylcellulose,hydroxypropylcellulose, sodium alginate, carbomer, povidone, acacia,guar gum, xanthan gum and tragacanth. Particularly preferred viscosityagents are methylcellulose, carbomer, xanthan gum, guar gum, povidone,sodium carboxymethylcellulose, and magnesium aluminum silicate.Pharmaceutical compositions of the invention generally include fromabout 0 to 5% of viscosity agents.

Preferred fillers include lactose, mannitol, sorbitol, tribasic calciumphosphate, diabasic calcium phosphate, compressible sugar, starch,calcium sulfate, dextro and microcrystalline cellulose. Pharmaceuticalcompositions of the invention generally contain from about 0 to 75% offillers.

Preferred lubricants/glidants include magnesium stearate, stearic acidand talc. Pharmaceutical compositions of the invention generally includefrom about 0 to 7%, preferably, about 1 to 5% of lubricants/glidants.

Preferred disintegrants include starch, sodium starch glycolate,crospovidone and croscarmelose sodium and microcrystalline cellulose.Pharmaceutical compositions of the invention generally include fromabout 0 to 20%, preferably, about 4 to 15% of disintegrants.

Preferred binders include acacia, tragacanth, hydroxypropylcellulose,pregelatinized starch, gelatin, povidone, hydroxypropylcellulose,hydroxypropylmethylcellulose, methylcellulose, sugar solutions, such assucrose and sorbitol, and ethylcellulose. Pharmaceutical compositions ofthe invention generally include from about 0 to 12%, preferably, about 1to 10% of binders.

Additional agents known to a skilled formulator may be combined with thecompounds of the invention to create a single dosage form.Alternatively, additional agents may be separately administered to amammal as part of a multiple dosage form.

For preparing pharmaceutical compositions containing the inventivecompounds, inert, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,dispersible granules, capsules, cachets and suppositories. The powdersand tablets may be comprised of from about 5 to 95 weight percent ofactive ingredient. Suitable solid carriers are known in the art, forexample, magnesium carbonate, magnesium stearate, talc, sugar andlactose. Tablets, powders, cachets and capsules can be used as soliddosage forms suitable for oral administration. Examples ofpharmaceutically-acceptable carriers and methods of manufacture forvarious compositions may be found in Remington's PharmaceuticalSciences, 18^(th) Ed., Mack Publishing Co. (1990), which is incorporatedin its entirety by reference herein.

Liquid form preparations include solutions, suspensions and emulsions.Common liquid form preparations include water and water-propylene glycolsolutions for parenteral injection or addition of sweeteners andopacifiers for oral solutions, suspensions and emulsions. Liquid formpreparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation include solutions andsolids in powder form, which may be combined with a pharmaceuticallyacceptable carrier, such as an inert compressed gas (e.g., nitrogen).

Also included are solid form preparations that may be converted, shortlybefore use, to liquid form preparations for either oral or parenteraladministration. Such liquid forms include solutions, suspensions andemulsions.

The compounds of the invention may also be delivered transdermally. Thetransdermal compositions can take the form of creams, lotions, aerosolsand emulsions and may be included in a transdermal patch of a matrix orreservoir type as is conventional in the art for this purpose.

The preferred mode of administering the compounds of the invention isoral. Preferably, the pharmaceutical preparation is in a unit dosageform. In such a form, the preparation is subdivided into suitable sizedunit doses containing appropriate quantities of the active component,for example, an effective amount to achieve the desired purpose.

The quantity of active ingredient (compound) in a unit dose ofpreparation may be varied or adjusted from about 0.01 to 4,000 mg,preferably, from about 0.02 to 1,000 mg, more preferably, from about 0.3to 500 mg, and most preferably, from about 0.04 to 250 mg, according tothe particular application. A typical recommended daily dosage regimenfor oral administration can range from about 0.02 to 2,000 mg/day, intwo to four divided doses. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.Typically, pharmaceutical compositions of the invention will beadministered from about 1 to 5 times per day, or alternatively, as acontinuous infusion. Such administration can be used as a chronic oracute therapy. The amount of active ingredient that may be combined withcarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Atypical preparation will contain from about 5 to 95% of active compound(w/w). Preferably, such preparations will contain from about 20 to 80wt. % of active compound.

The pharmaceutically-acceptable carriers employed in conjunction withthe compounds of the present invention are used at a concentrationsufficient to provide a practical size to dosage relationship. Thepharmaceutically-acceptable carriers, in total, may comprise from about0.1 to 99.9% by weight of the pharmaceutical compositions of theinvention, preferably, from about 20 to 80% by weight.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination of the invention may beadministered, if necessary. Subsequently, the dosage or frequency oradministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained. When thesymptoms have been alleviated to the desired level, treatment shouldcease. Patients may, however, require intermittent treatment on along-term basis upon any recurrence of disease symptoms.

Specific dosage and treatment regimens for any particular patient may bevaried and will depend upon a variety of factors, including the activityof the specific compound employed, the age, body weight, general healthstatus, sex and diet of the patient, the time of administration, therate of excretion, the specific drug combination, the severity andcourse of the symptoms being treated, the patient's disposition to thecondition being treated and the judgment of the treating physician.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. The amount and frequency of theadministration of compounds of the invention or their pharmaceuticallyacceptable salts may be regulated according to the judgment of theattending clinician, based on the factors recited above. As a skilledartisan will appreciate, lower or higher doses than those recited abovemay be required.

For example, it is often the case that a proper dosage level is based onthe weight of the patient. For instance, dosage levels of between about0.01 and 100 mg/kg of body weight per day, preferably, between about 0.5and 75 mg/kg of body weight per day, and more preferably, between about1 and 50 mg/kg of body weight per day, of the inventive compounds,compositions and salts thereof described herein, are therapeuticallyuseful for the treatment of a variety of biological disorders,particularly, male and female sexual dysfunction. Between two patientsof differing weights, a higher dosage will be used for the heavierpatient, all other things being equal.

The inventive compounds are understood to provide efficacious treatmentof (male) erectile dysfunction, including a reasonable time of onsetupon administration, and a reasonable duration after administration. Forexample, in the treatment of erectile dysfunction, a dosage of theinventive compound may be taken about an hour before a sex act is to beundertaken. Particular dosages will work within about thirty minutes oftheir administration. Ideal dosages will affect a patient within aboutfifteen minutes of their administration. While food, diet, pre-existingconditions, alcohol and other systemic conditions could lengthen thetime delay for an inventive drug to work after its administration, it isunderstood that optimum dosages in combination with sexual stimulationwill result in an efficacious drug treatment within and for a reasonableamount of time.

The inventive compounds can exist in unsolvated as well as solvatedforms, including hydrated forms. In general, the solvated forms, withpharmaceutically-acceptable solvents, such as water, ethanol and thelike, are equivalent to the unsolvated forms for purposes of thisinvention.

The inventive compounds may form pharmaceutically-acceptable salts withorganic and inorganic acids. Examples of suitable acids for saltformation are hydrochloric, sulfuric, phosphoric, acetic, citric,malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic,methanesulfonic and other mineral and carboxylic acids well known tothose skilled in the art. The salts are prepared by contacting the freebase forms with a sufficient amount of the desired acid to produce asalt in a conventional manner. The free base forms may be regenerated bytreating the salt with a suitable dilute aqueous base solution, such asdilute aqueous sodium hydroxide, potassium carbonate, ammonia or sodiumbicarbonate. The free base forms may differ somewhat from theirrespective salt forms in certain physical properties, such as solubilityin polar solvents, but the salts are otherwise equivalent to theirrespective free base forms for purposes of the invention.

The invention comprises a compound having the formula (I) or (II), amethod for making an inventive compound, a method for making apharmaceutical composition from at least one inventive compound and atleast one pharmaceutically-acceptable carrier, and a method of using oneor more inventive compounds to treat a variety of disorders, symptomsand diseases.

The inventive compounds and their pharmaceutically-acceptable salt andneutral compositions may be formulated together with apharmaceutically-acceptable carrier. The resulting composition may beadministered in vivo to mammals, such as men or women, to treat avariety of disorders, symptoms and diseases. For example, the inventivecompounds and compositions may be used to treat diseases of theurogenital system, specifically, male erectile dysfunction (e.g.,impotence) and female sexual dysfunction. Male erectile dysfunction maybe defined as an inability of the male to sufficiently obtain and/orsustain an erection to have intercourse with his mate. In the treatmentof erectile dysfunction, it is believed that the inventive PDE Vinhibitors of formulas (I) and (II) are beneficial therapeutic agentsbecause they elevate cGMP levels in the human body. This actionfacilitates corpus cavernosum smooth muscle relaxation, which providesan increased flow of blood therein and results in an erection. Thismakes the inventive compounds especially useful for treating impotenceand other types of diseases that are affected by cGMP levels.

Accordingly, another aspect of the invention is a method for treatingerectile dysfunction in a mammal in need of such treatment, comprisingadministering to the mammal at least one compound having the formula (I)or (II) or a pharmaceutical composition thereof in an amount effectiveto ameliorate and/or reduce one or more of the symptoms associated witherectile dysfunction sufficiently enough so that the mammal can completeintercourse with another mammal.

Introduced in 1998 as the first pill to treat impotence, Viagra® todayis the most commonly prescribed medication to treatphysiologically-caused erectile dysfunction (“ED”). Certain patients,however, can experience undesirable side effects while taking Viagra®.For instance, the use of Viagra® is contraindicated to patients who areusing organic nitrates, either regularly or intermittently. Physicians'Desk Reference®, 55^(th) Ed, pp. 2534-37 (2001). Combining Viagra® withnitrates can cause a hypotensive episode or suddenly reduce bloodpressure to dangerous levels, which may cause a heart attack. Id.Accordingly, men who have a heart condition that requires the use ofnitrate drugs should not use Viagra®. Id. It has also been reported thatViagra® can cause a vision side effect by impairing the patient's colordiscrimination (blue/green), causing a “blue-halo” light visualalteration. Id. This side effect is presumably due to inhibition of thePDE VI isoenzyme (found in a retina). Id.

An advantage of the inventive compounds is that they can be particularlyselective for the PDE V isoenzyme in comparison to other types of PDEisoenzymes, such as the PDE VI isoenzyme. It is believed that thisincreased selectivity will ameliorate side effects associated with theuse of Viagra®. In particular, the high selectivity of the inventivecompounds should minimize, and may even prevent, the occurrence of a“blue-halo” light visual alteration. It is believed that the increasedisoenzyme selectivity in inhibiting PDE V isoenzyme (found in a penis)versus PDE VI isoenzyme (found in a retina) accounts for obviating the“blue-halo” visual side effect.

The compounds of the present invention may be employed alone or incombination with other agents, particularly, other types of PDEinhibitors (especially cGMP PDE V inhibitors), prostanoids, α-adrenergicreceptor, dopamine receptor agonists, melanocortin receptor agonists,endothelin receptor antagonists, endotheolin converting enzymeinhibitors, angiotensin II receptor antagonists, angiotensin convertingenzyme inhibitors, neutral metalloendopeptidase inhibitors, renininhibitors, serotonin 5-HT_(2c) receptor agonists, nociceptin receptoragonists, rho kinase inhibitors, potassium channel modulators andinhibitors of multidrug resistance protein 5.

Examples of therapeutic agents that may be used in combination withcompounds of the invention are the following: PDE V inhibitors, such assildenafil citrate (Viagra®, Pfizer, Connecticut, United States),Vardenafil™ (Bayer, Germany) and IC-351 (Cialis™, Lilly-ICOS, Washingtonand Indiana, United States); prostanoids, such as prostaglandin E₁;α-adrenergic agonists, such as phentolamine mesylate; dopamine receptoragonists, such as apomorphine; angiotensin II antagonists, such aslosartan, irbesartan, valsartan and candesartan; and ETA antagonists,such as bosentan and ABT-627.

It is understood that other combinations may be undertaken whileremaining within the scope of the invention. While one or more of theinventive compounds may be used in an application of monotherapy totreat erectile dysfunction, they also may be used in combinationtherapy, in which the inventive compounds are combined with one or moreother pharmaceutical compounds that are useful for treating erectiledysfunction and/or other types of disorders, symptoms and diseases.

As discussed above, due to their cGMP-PDE V inhibitory activities, theinventive compounds are useful for treating urological disorders, inparticular, female and male sexual dysfunctions. Other physiologicaldisorders, symptoms and diseases can also benefit from cGMP-PDE Vinhibition. More specifically, the inventive compounds, salts andderivatives thereof may be used to treat cardiovascular andcerebrovascular diseases, angina pectoris, hypertension, restenosis postangioplasty, endarterectomy, stent introduction, peripheral vasculardiseases, cerebral stroke, respiratory tract disorders, such asreversible airway obstruction, chronic asthma and bronchitis, allergicdisorders associated with atopy, such as urticaria, eczema, and rinitis,pulmonary hypertension, ischemic heart diseases, impaired glucosetolerance, diabetes and related complications, insulin resistancesyndrome, hyperglycemia, polycystic ovarian syndrome, glomerulardiseases, renal insufficiency, nephritis, tubular interstitial disease,autoimmune diseases, glaucoma, intestinal motility disorders, cachexiaand cancer.

Another aspect of this invention is to provide a kit comprising separatecontainers in a single package, wherein the inventive pharmaceuticalcompounds, compositions and/or salts thereof are used in combinationwith pharmaceutically-acceptable carriers to treat disorders, symptomsand diseases where cGMP-PDE V inhibition plays a role.

It is understood that other combinations may be undertaken whileremaining within the scope of the invention. While one or more of theinventive compounds may be used in an application of monotherapy totreat erectile dysfunction, they also may be used in combinationtherapy, in which the inventive compounds are combined with one or moreother pharmaceutical compounds that are useful for treating erectiledysfunction and/or other types of disorders, symptoms and diseases.

As discussed above, due to their cGMP-PDE-V inhibitory activities, theinventive compounds are useful for treating urological disorders, inparticular, female and male sexual dysfunctions. Other physiologicaldisorders, symptoms and diseases can also benefit from cGMP-PDE Vinhibition. More specifically, the inventive compounds, salts andderivatives thereof may be used to treat cardiovascular andcerebrovascular diseases, angina pectoris, hypertension, restenosis postangioplasty, endarterectomy, stent introduction, peripheral vasculardiseases, cerebral stroke, respiratory tract disorders, such asreversible airway obstruction, chronic asthma and bronchitis, allergicdisorders associated with atopy, such as urticaria, eczema, and rinitis,pulmonary hypertension, ischemic heart diseases, impaired glucosetolerance, diabetes and related complications, insulin resistancesyndrome, hyperglycemia, polycystic ovarian syndrome, glomerulardiseases, renal insufficiency, nephritis, tubular interstitial disease,autoimmune diseases, glaucoma, intestinal motility disorders, cachexiaand cancer.

Another aspect of this invention is to provide a kit comprising separatecontainers in a single package, wherein the inventive pharmaceuticalcompounds, compositions and/or salts thereof are used in combinationwith pharmaceutically-acceptable carriers to treat disorders, symptomsand diseases where cGMP-PDE V inhibition plays a role.

The above description is not intended to detail all modifications andvariations of the invention. It will be appreciated by those skilled inthe art that changes can be made to the embodiments described abovewithout departing from the inventive concept. It is understood,therefore, that the invention is not limited to the particularembodiments described above, but is intended to cover modifications thatare within the spirit and scope of the invention, as defined by thelanguage of the following claims.

1. A compound of Formula (I), an enantiomer, stereoisomer, rotomer,tautomer or a pharmaceutically acceptable salt thereof:

where, (a) R¹ and R² are, independently of one another, each a C₁₋₁₅alkyl group, branched or straight chain, unsubstituted or substitutedwith one or more substituents, a C₂₋₁₅ alkenyl group, branched orstraight chain, unsubstituted or substituted with one or moresubstituents, a C₂₋₁₅ alkynyl group, branched or straight chain,unsubstituted or substituted with one or more substituents, a C₃₋₁₅cycloalkyl group, unsubstituted or substituted with one or moresubstituents, an arylalkyl group, unsubstituted or substituted with oneor more substituents, an aryl group, unsubstituted or substituted withone or more substituents, a heteroaryl group, unsubstituted orsubstituted with one or more substituents, —OR⁵, —COOR⁵, —C(O)R⁵ or—C(O)N(R⁵)₂, where, R⁵ is a hydrogen atom or a hydrocarbon radical,unsubstituted or substituted with one or more substituents, or one of R¹and R² is a hydrogen atom and the other one of R¹ and R² is defined thesame as above; (b) R³ is an aryl group, unsubstituted or substitutedwith one or more substituents, a heteroaryl group, unsubstituted orsubstituted with one or more substituents, or a heterocyclic grouphaving 1 to 3 heteroatoms fused to a 5- or 6-membered aryl ring,unsubstituted or substituted with one or more substituents, with theproviso that R³ is not an aryl group substituted at its para positionwith a —Y-aryl group, where, Y is a carbon-carbon single bond, —C(O)—,—O—, —S—, —N(R²¹)—, —C(O)N(R²²)—, —N(R²²)C(O)—, —OCH₂—, —CH₂O—, —SCH₂—,—CH₂S—, —N(H)C(R²³)(R²⁴)—, —N(R²³)S(O₂)—, —S(O₂)N(R²³)—,—C(R²³)(R²⁴)N(H)—, —CH═CH—, —CF═CF—, —CH═CF—, —CF═CH—, —CH₂CH₂—,—CF₂CF₂—,

where, R²¹ is a hydrogen atom or a —CO(C₁₋₄ alkyl), C₁₋₆ alkyl, allyl,C₃₋₆ cycloalkyl, phenyl or benzyl group; R²² is a hydrogen atom or aC₁₋₆ alkyl group; R²³ is a hydrogen atom or a C₁₋₅ alkyl, aryl or—CH₂-aryl group; R²⁴ is a hydrogen atom or a C₁₋₄ alkyl group; R²⁵ is ahydrogen atom or a C₁₋₈ alkyl, C₁₋₈ perfluoroalkyl, C₃₋₆ cycloalkyl,phenyl or benzyl group; R²⁶ is a hydrogen atom or a C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl or benzyl group; R²⁷ is —NR²³R²⁴, —OR²⁴, —NHCONH₂,—NHCSNH₂,

and R²⁸ and R²⁹ are, independently of one another, each a C₁₋₄ alkylgroup or, taken together with each other, a —(CH₂)_(q) group, where q is2 or 3; and (c) R⁴ is a heterocycloalkyl group of 3 to 15 membersunsubstituted or substituted with one or more substituents; wherein, theone or more substituents for all the groups are chemically-compatibleand are, independently of one another, each an: alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, heteroaryl,heterocycloalkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl,alkylthioalkyl, carboxyalkyl, imidazolylalkyl, indolylalkyl, mono-, di-and trihaloalkyl, mono-, di- and trihaloalkoxy, amino, alkylamino,dialkylamino, alkoxy, hydroxy, halo, nitro, oximino, —COOR⁵⁰, —COR⁵⁰,—SO₀₋₂R⁵⁰, —SO₂NR⁵⁰R⁵¹, NR⁵²SO₂R⁵⁰, ═C(R⁵⁰R⁵¹), ═N—OR⁵⁰, ═N—CN,═C(halo)₂, ═S, ═O, —CON(R⁵⁰R⁵¹), —OCOR⁵⁰, —OCON(R⁵⁰R⁵¹), —N(R⁵²)CO(R⁵⁰),—N(R⁵²)COOR⁵⁰ or —N(R⁵²)CON(R⁵⁰R⁵¹) group, where: R⁵⁰, R⁵¹ and R⁵² are,independently of one another, each a hydrogen atom or a branched orstraight-chain, optionally substituted, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,C₄₋₆ heterocycloalkyl, heteroaryl or aryl group, or R⁵⁰ and R⁵¹ togetherwith the atom to which they are attached together form a carbocyclic orheterocyclic ring system, wherein the optional substituents are definedabove for the one or more substituents.
 2. The compound according toclaim 1, where, R¹ is an alkyl or aryl group, with or without the one ormore substituents.
 3. The compound according to claim 1, where, R¹ is amethyl, ethyl or benzyl group, with or without the one or moresubstituents.
 4. The compound according to claim 1, where, R² is analkyl group, with or without the one or more substituents.
 5. Thecompound according to claim 4, where, R² is a methyl, ethyl, iso-butylor hydroxyethyl group, with or without the one or more substituents. 6.The compound according to claim 1, where, R³ is an at group, with orwithout the one or more substituents.
 7. The compound according to claim6, where, R³ is a hydroxyaryl, alkoxyaryl or aminosulfonylaryl group,with or without the one or more substituents.
 8. The compound accordingto claim 7, where, the hydroxyaryl, alkoxyaryl or aminosulfonylarylgroup for R³ is substituted with at least one halogen atom on the arylring.
 9. The compound according to claim 1, where R⁴ is atetrahydropyranyl group, with or without one or more substituents. 10.The compound according to claim 8, where, R⁴ is a tetrahydropyranylgroup, with or without the one or more substituents.
 11. The compoundaccording to claim 1, where, R¹ is a methyl or ethyl group, R² is amethyl, ethyl or hydroxyethyl group, R³ is a 3-chloro-4-hydroxyphenyl,3-bromo-4-hydroxyphenyl, 3-chloro-4-methoxyphenyl,3-bromo-4-methoxyphenyl, or 4-aminosulfonylphenyl group and R⁴ is atetrahydropyranyl group.
 12. The compound according to claim 1, whichis:


13. The compound according to claim 1, which is:


14. A method for elevating a cGMP level in a patient in need of thetreatment, comprising administering to the patient an effective amountof the compound according to claim
 1. 15. A method for treating anerectile dysfunction in a patient in need of the treatment, comprisingadministering to the patient an effective amount of at least one of thecompound according to claim
 1. 16. A method for treating an erectiledysfunction in a patient in need of the treatment, comprisingadministering to the patient a combination therapy, comprising atherapeutically effective amount of at least one compound according toclaim 1 and at least one compound selected from the group consisting of:a prostanoid dopamine receptor agonist, melanocortin receptor agonist,endothelin receptor antagonist, endothelin converting enzyme inhibitor,angiotensin II receptor antagonist, angiotensin converting enzymeinhibitor, neutral metalloendopeptidase inhibitor, renin inhibitor,serotonin 5-HT_(2c) receptor agonist, nociceptin receptor agonist, rhokinase inhibitor, potassium channel modulator and multidrug resistanceprotein 5 inhibitor.
 17. A pharmaceutical composition comprising acompound, enantiomer, stereoisomer, rotomer or tautomer of claim 1 orpharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 18. The pharmaceutical composition according toclaim 17, wherein the compound is:


19. A method for producing a compound having the formula (I),comprising: (i) reacting a compound having the formula (III) withL-halide in the presence of a base to form a compound having the formula(IV):

where, (a) R¹ is a hydrogen atom or a C₁₋₁₅ alkyl group, branched orstraight chain, unsubstituted or substituted with one or moresubstituents, a C₂₋₁₅ alkenyl group, branched or straight chain,unsubstituted or substituted with one or more substituents, a C₂₋₁₅alkynyl group, branched or straight chain, unsubstituted or substitutedwith one or more substituents, a C₃₋₁₅ cycloalkyl group, unsubstitutedor substituted with one or more substituents, an arylalkyl group,unsubstituted or substituted with one or more substituents, an arylgroup, unsubstituted or substituted with one or more substituents, aheteroaryl group, unsubstituted or substituted with one or moresubstituents, —OR⁵, —COOR⁵, —C(O)R⁵ or —C(O)N(R⁵)₂, where R⁵ is ahydrogen atom or a hydrocarbon radical, branched or straight-chain,unsubstituted or substituted with one or more substituents; (b) L is R²a protected form of R²; and (c) Ph is a phenyl group; (ii) debenzylatingand then reading the compound having the formula (IV) with a halidehaving the formula XCH₂R³ to form the compound having the formula (V):

where, X is a halogen atom and R³ is an aryl group, unsubstituted orsubstituted with one or more substituents, a heteroaryl group,unsubstituted or substituted with one or more substituents, or aheterocyclic group having 1 to 3 heteroatoms fused to a 5- or 6-memberedaryl ring, unsubstituted or substituted with one or more substituents,with the proviso that R³ is not an aryl group substituted at its paraposition with a —Y-aryl group, where Y is a carbon-carbon single bond,—CO—, —O—, —S—, —N(R²¹)—, —CON(R²²)—, —N(R²²)CO—, —OCH₂—, —CH₂O—,—SCH₂—, —CH₂S—, —NHC(R²³)(R²⁴)—, —NR²³SO₂—, —SO₂NR²³—, —C(R²³)(R²⁴)NH—,—CH═CH—, —CF═CF—, —CH═CF—, —CF═CH—, —CH₂CH₂—, —CF₂CF₂—,

where, R²¹ is a hydrogen atom or a —CO(C₁₋₄ alkyl), C₁₋₆ alkyl, C₃₋₆cycloalkyl, pherlyl or benzyl group; R²² is a hydrogen atom or a C₁₋₄alkyl group; R²³ is a hydrogen atom or a C₁₋₅ alkyl, aryl or —CH₂-arylgroup; R²⁴ is a hydrogen atom or a C₁₋₄ alkyl group; R²⁵ is a hydrogenatom or a C₁₋₈ alkyl, C₁₋₈ perfluoroalkyl; C₃₋₆ cycloalkyl, phenyl orbenzyl group; R²⁶ is a hydrogen atom or a C₁₋₆ alkyl, C₃₋₆ cycloalkyl,phenyl or benzyl group; R²⁷ is —NR²³R²⁴, —OR²⁴, —NHCONH₂, —NHCSNH₂,

and R²⁸ and R²⁹ are, independently of one another, each a C₁₋₄ alkylgroup, or R²⁸ and R²⁹, taken together with each other, are a —(CH₂)_(q)group, where q is 2 or 3; wherein, R²¹ through R²⁹ are optionallysubstituted with one or more substituents; and (iii) deprotonating andthen halogenating the compound having the formula (V) to form a compoundhaving the formula (VI):

where, Hal is a halogen atom; (iv) reacting the compound having theformula (VI) with an amine having the formula R⁴NH₂ to form a compoundhaving the formula (VII):

where, R⁴ is a heterocycloalkyl group of 3 to 15 members, with orwithout unsubstituted or substituted with one or more substituents; and(v) removing the protecting portion of L, when L is the protected formof R², on the compound having the formula (VII) to form the compoundhaving the formula (I):

where, R² is defined the same as R¹ above, with the proviso that atleast one of R¹ and R² is not a hydrogen atom; wherein, the one or moresubstituents for all the groups are chemically-compatible and are,independently of one another, each an: alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, heteroaryl,heterocycloalkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl,alkylthioalkyl, carboxyalkyl, imidazolylalkyl, indolylalkyl, mono-, di-and trihaloalkyl, mono-, di- and trihaloalkoxy, amino, alkylamino,dialkylamino, alkoxy, hydroxy, halo, nitro, oximino, —COOR⁵⁰, —COR⁵⁰,—SO₀₋₂R⁵⁰, —SO₂NR⁵⁰R⁵¹, NR⁵²S₂R⁵⁰, ═C(R⁵⁰R⁵¹), ═N—OR⁵⁰, ═N—CN,═C(halo)₂, ═S, ═O, —CON(R⁵⁰R⁵¹), —OCOR⁵⁰, —OCON(R⁵⁰R⁵¹), —N(R⁵²)CO(R⁵⁰),—N(R⁵²)COOR⁵⁰ or —N(R⁵²)CON(R⁵⁰R⁵¹) group, where: R⁵⁰, R⁵¹ and R⁵² are,independently of one another, each a hydrogen atom or a C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₄₋₆ heterocycloalkyl, heteroaryl and aryl group, or R⁵⁰ andR⁵¹ together with the atom to which they are attached together form acarbocyclic or heterocyclic ring system, wherein the optionalsubstituents are defined above for the one or more substituents.
 20. Thepharmaceutical composition according to claim 17, which furthercomprises at least one compound selected from the group consisting of aprostanoid, dopamine receptor antagonist melanocortin receptor agonist,endothelin receptor antagonist, endothelin converting enzyme inhibitor,angiotensin II receptor antagonist, angiotensin converting enzymeinhibitor, neutral metalloendopeptidase inhibitor, renin inhibitor,serotonin 5-HT_(2c) receptor agonist, nociceptin receptor agonist, rhokinase inhibitor, potassium channel modulator and multidrug resistanceprotein 5 inhibitor.
 21. The pharmaceutical composition according toclaim 20 where the second compound is an endothelin receptor antagonist.22. The compound according to claim 1, where, R¹ is an alkyl or arylgroup, with or without the one or more substituents, R² is an alkylgroup, with or without the one or more substituents, and R³ is a4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 3-bromo-4-hydroxyphenyl,4-methoxyphenyl, 3-chloro-4-methoxyphenyl, 3-bromo-4-methoxyphenyl,4-aminosulfonylphenyl, 3-chloro-4-aminosulfonylphenyl or3-bromo-4-aminosulfonylphenyl group.